INDUSTRIAL    CHEMISTRY 

BEING    A    SERIES    OF    VOLUMES    GIVINi 
A    COMPREHENSIVE    SURV^v    OF 

THE    CHEMICAL   INDUSTRIE^ 


INDUSTRIAL    CHEMISTRY 

BEING   A   SERIES   OF  VOLUMES   GIVING   A 
COMPREHENSIVE   SURVEY   OF 

THE    CHEMICAL    INDUSTRIES 

EDITED  BY  SAMUEL  RIDEAL,  D.Sc.  LOND.,  F.I.C. 

FELLOW  OF   UNIVERSITY  COLLEGE,   LONDON 

ASSISTED   BY 

JAMES  A.  AUDLEY,  B.Sc.,  F.I.C.  J.  R.  PARTINGTON,  M.A.,  PH.D. 

W.  BACON,  B.Sc.,  F.I.C.,  F.C.S.  ARTHUR  E.  PRATT, B.Sc.,  Assoc.R.S.M. 

E.  DE  BARRY  BARNETT,  B.Sc.,  A.I.C.  ERIC  K.  RIDEAL,  M.B.E.,  D.Sc.,  M. A., 
M.  BARROWCLIFF,  M.B.E.,  F.I.C.  PH.D.,  F.I.C. 

H.  GARNER  BENNETT,  M.Sc.  W.  H.  SIMMONS,  B.Sc.,  F.I.C. 

F.  H.  CARR,  C.B.E.,  F.I.C.  R.  W.  SINDALL,  F.C.S. 

S.  HOARE   COLLINS,  M.Sc.,  F.I.C.  HUGH  S.  TAYLOR,  D.Sc. 

H.   C.  GREENWOOD,    O.B.E.,  D.Sc.,  ARM  AND  DE  WAELE,  B.Sc. 

F.I.C.  C.  M.  WHITTAKER,  B.Sc. 
R.  S.  MORRELL,  M.A.,  PH.D.  &c.,  &c. 


ORGANIC    MEDICINAL 
CHEMICALS 

(SYNTHETIC   AND    NATURAL) 


BY 

M.   BARROWCLIFF,  M.B.E.,  F.I.C. 

"I 

AND 

FRANCIS    H.    CARR,    C.B.E.,    F.I.C 


NEW  YORK 
D.    VAN    NOSTRAND    COMPANY 

EIGHT   WARREN   STREET 
1920 


PRINTED   IN  GREAT  BRITAIN 


GENERAL    PREFACE 

THE  rapid  development  of  Applied  Chemistry  in  recent  years 
has  brought  about  a  revolution  in  all  branches  of  technology. 
This  growth  has  been  accelerated  during  the  war,  and  the 
British  Empire  has  now  an  opportunity  of  increasing  its 
industrial  output  by  the  application  of  this  knowledge  to  the 
raw  materials  available  in  the  different  parts  of  the  world. 
The  subject  in  this  series  of  handbooks  will  be  treated  from 
the  chemical  rather  than  the  engineering  standpoint.  The 
industrial  aspect  will  also  be  more  prominent  than  that  of 
the  laboratory.  Bach  volume  will  be  complete  in  itself,  and 
will  give  a  general  survey  of  the  industry,  showing  how 
chemical  principles  have  been  applied  and  have  affected 
manufacture.  The  influence  of  new  inventions  on  the 
development  of  the  industry  will  be  shown,  as  also  the 
effect  of  industrial  requirements  in  stimulating  invention. 
Historical  notes  will  be  a  feature  in  dealing  with  the 
different  branches  of  the  subject,  but  they  will  be  kept 
within  moderate  limits.  Present  tendencies  and  possible 
future  developments  will  have  attention,  and  some  space 
will  be  devoted  to  a  comparison  of  industrial  methods  and 
progress  in  the  chief  producing  countries.  There  will  be  a 
general  bibliography,  and  also  a  select  bibliography  to  follow 
each  section.  Statistical  information  will  only  be  introduced 
in  so  far  as  it  serves  to  illustrate  the  line  of  argument. 

Each  book  will  be  divided  into  sections  instead  of 
chapters,  and  the  sections  will  deal  with  separate  branches 
of  the  subject  in  the  manner  of  a  special  article  or  mono- 
graph. An  attempt  will,  in  fact,  be  made  to  get  away  from 

V 

453551 


vi  GENERAL    PREFACE 

the  orthodox  textbook  manner,  not  only  to  make  the  treat- 
ment original,  but  also  to  appeal  to  the  very  large  class  of 
readers  already  possessing  good  textbooks,  of  which  there 
are  quite  sufficient.  The  books  should  also  be  found  useful 
by  men  of  affairs  having  no  special  technical  knowledge,  but 
who  may  require  from  time  to  time  to  refer  to  technical 
matters  in  a  book  of  moderate  compass,  with  references  to 
the  large  standard  works  for  fuller  details  on  special  points 
if  required. 

To  the  advanced  student  the  books  should  be  especially 
valuable.  His  mind  is  often  crammed  with  the  hard  facts 
and  details  of  his  subject  which  crowd  out  the  power  of 
realizing  the  industry  as  a  whole.  These  books  are  intended 
to  remedy  such  a  state  of  affairs.  While  recapitulating  the 
essential  basic  facts,  they  will  aim  at  presenting  the  reality 
of  the  living  industry.  It  has  long  been  a  drawback  of  our 
technical  education  that  the  college  graduate,  on  commencing 
his  industrial  career,  is  positively  handicapped  by  his 
academic  knowledge  because  of  his  lack  of  information  on 
current  industrial  conditions.  A  book  giving  a  compre- 
hensive survey  of  the  industry  can  be  of  very  material 
assistance  to  the  student  as  an  adjunct  to  his  ordinary  text- 
books, and  this  is  one  of  the  chief  objects  of  the  present 
series.  Those  actually  engaged  in  the  industry  who  have 
specialized  in  rather  narrow  limits  will  probably  find  these 
books  more  readable  than  the  larger  textbooks  when  they 
wish  to  refresh  their  memories  in  regard  to  branches  of  the 
subject  with  which  they  are  not  immediately  concerned. 

The  volume  will  also  serve  as  a  guide  to  the  standard 
literature  of  the  subject,  and  prove  of  value  to  the  con- 
sultant, so  that,  having  obtained  a  comprehensive  view  of 
the  whole  industry,  he  can  go  at  once  to  the  proper 
authorities  for  more  elaborate  information  on  special  points, 
and  thus  save  a  couple  of  days  spent  in  hunting  through  the 
libraries  of  scientific  societies. 

As  far  as  this  country  is  concerned,  it  is  believed  that 
the  general  scheme  of  this  series  of  handbooks  is  unique, 
and  it  is  confidently  hoped  that  it  will  supply  mental 


GENERAL   PREFACE  vii 

munitions  for  the  coming  industrial  war.  I  have  been 
fortunate  in  securing  writers  for  the  different  volumes  who 
are  specially  connected  with  the  several  departments  of 
Industrial  Chemistry,  and  trust  that  the  whole  series  will 
contribute  to  the  further  development  of  applied  chemistry 
throughout  the  Empire. 

SAMUEL   RIDEAI* 


PREFACE 

THE  section  of  the  British  Chemical  Industry  concerned 
with  the  manufacture  of  Synthetic  Medicinal  Chemicals 
calls  for  most  earnest  attention.  It  is  unnecessary  here 
to  discuss  its  importance,  which  becomes  ever  greater  with 
the  advance  of  our  knowledge. 

Creditable  as  was  the  accomplishment  of  British  chemists 
during  the  war  in  supplying  within  a  short  space  of  time 
most  of  the  important  synthetic  medicinal  chemicals,  these 
manufactures  were  not  in  every  case  established  on  an 
economic  basis.  In  order  to  do  this,  it  is  of  outstanding 
importance  to  perfect  processes  so  that  the  most  economical 
methods  are  used  and  the  best  possible  yields  obtained ; 
and  such  perfection  can  only  be  attained  by  zealous  work 
on  the  part  of  men  with  knowledge. 

It  is  hoped  that  the  material  here  collected  will  prove 
of  value  to  chemists  engaged  in  this  work,  as  well  as  to 
those  responsible  for  the  education  of  the  men  whose  task 
in  the  era  which  is  dawning  will  be  the  application  of 
chemical  science  to  industry. 

No  attempt  has  been  made  to  deal  with  all  the  known 
synthetic  remedies,  very  many  of  which  are  non-essential, 
and  of  yet  others  too  little  is  known  to  permit  a  true 
judgment  of  their  value.  Similarly,  reference  has  been 
omitted  to  very  numerous  processes  which  do  not  seem 
capable  of  practical  application.  "  Blocking "  patents, 
when  referred  to,  are  not  described  in  detail. 

The  authors  recognise  the  incompleteness  of  some  of 
the  descriptions  given.  To  this  shortcoming  limitations 


x  PREFACE 

of  space  have  contributed,  but   chiefly   it  is  due  to  the 
insufficiency  of  published  accounts. 

The  various  chemicals  dealt  with  are  for  the  most  part 
grouped  in  sections  according  to  their  therapeutic  uses. 
Such  an  arrangement  is  considered  by  the  authors  to  be 
the  most  convenient,  though  this  classification  is  superficial 
and  rests  on  little  or  no  scientific  foundation. 

The  authors  wish  most  gratefully  to  acknowledge  assist- 
ance given  by  H.M.  Explosives  Department  of  the  Ministry 
of  Munitions  for  an  account  of  the  manufacture  of  ether ; 
to  the  Royal  Society's  Committee  for  various  processes 
worked  out  in  the  Universities ;  and  to  the  following  engi- 
neering firms  who  have  supplied  photographs  and  drawings 
of  plant:  Messrs.  E.  Barbet  et  Cie.,  W.  J.  Fraser  &  Co., 
Manlove  Alliot  &  Co.,  and  The  Standard  Chemical  Engi- 
neering Co.  Acknowledgments  are  also  due  to  Ullmann's 
"  Enzyklopsedie,"  from  which  the  authors  have  received 
assistance,  and  to  the  authors  of  very  many  other  standard 
works,  notably  to  Prof.  Cushny  and  Dr.  Cain. 

M.  B. 
F.  H.  C. 

November,   1920. 


CONTENTS 


PAGE 

GENERAL  PREFACE      ....  v 

PREFACE .  ix 

CONTENTS xi 

LIST  OF   ILLUSTRATIONS  .  xiii 


INTRODUCTION I 

SECTION    I.— NARCOTICS   AND    GENERAL 
ANESTHETICS. 

General ;  ether,  methylal,  paraldehyde,  acetophenone,  ethyl  chloride,  ethyl 
bromide,  chloroform,  chloral  hydrate,  chloralose,  chloral  formamide, 
butyl  chloral  hydrate,  chloretone,  sulphonal,  trional,  tetronal,  urethane, 
hedonal,  adalin,  veronal,  bromural,  neuronal  .....  8 


SECTION   II.— NATURALLY    OCCURRING 
ALKALOIDS   AND   THEIR   DERIVATIVES. 

General ;  morphine,  codeine,  apomorphine,  narcotine,  cotarnine,  papa- 
verine,  hydrastine,  hydrastinine,  emetine,  hyoscyamine,  atropine, 
hyoscine,  homatropine,  quinine,  cinchonine,  cinchonidine,  quinidine, 
strychnine,  brucine,  pilocarpine,  sparteine,  eserine,  colchicine,  aconitine  49 


SECTION  III.— NATURAL  AND   SYNTHETIC 
LOCAL  ANESTHETICS. 

General;    cocaine,  tropacocaine,  j8-eucaine,  stovaine,  alypine,  novocaine, 

anaesthesine,  nirvanine    .......         .         .89 


SECTION  IV— ANTIPYRETICS  AND  ANALGESICS. 

General;    acetanilide,  exalgin,  phenacetin,  lactophenin,  antipyrine,  pyra- 

midon,  benzoic  acid,  salicylic  acid,  methyl  salicylate,acetyl  salicylic  acid     113 

xi 


xii  CONTENTS 

SECTION    V.— ORGANIC   ANTISEPTICS   AND 
DISINFECTANTS. 

PAGE 

General  j  phenol,  salol,  resorcinol,  acetylresorcinol,  guaiacol,  guaiacol 
carbonate,  potassium  guaiacol  sulphonate,  thymol,  beta-naphthol, 
chloramine-T,  dichloramine-T,  halazone,  tribromphenol,  iodoform, 
tetra-iodo  pyrrol,  iodipin,  sozoiodol,  aristol,  loretin,  sajodin,  nosophen, 
formaldehyde,  hexamine,  proflavine,  acriflavine,  malachite  green, 
chinosol,  tannalben,  tannoform,  santalol,  santalol  carbonate,  allosan  .  146 


SECTION   VI.— PURGATIVES. 

General ;    aloin,    cascara  sagrada,    rhubarb,   exodin,    chrysarobin,   senna, 

celocynth,  jalap,  scammony,  podophyllin,  phenolphthalein          .         .     197 


SECTION   VII.— VASO-CONSTRICTORS  AND 
VASO-DILATORS. 

General ;  ergotoxine,  ergotinine,  tyramine,  histamine,  adrenaline,  «thyl 
nitrite,  amyl  nitrite,  nitroglycerin,  erythrol  tetranitrate,  mannitol 
hexanitrate  .  .  .  .  .  .  .  .  .  .  .211 


SECTION  VIII.— DIURETICS  AND   URIC   ACID 
SOLVENTS. 

General ;  caffeine,  theophylline,  theobromine,  piperazine,  atophan      .         .     230 


SECTION   IX.— ORGANO-METALLIC  COMPOUNDS. 

General  j  atoxyl,  arseno-phenyl-glycine,  salvarsan,  neosalvarsan,  luargol, 
galyl,  sulphoform,  protargol,  argonin,  mercury  salicylate,  mercury 
succinimide 256 


SECTION  X.— THE  DIGITALIS  GROUP,  SKIN 

IRRITANTS    GLUCOSIDES    AND 

NEUTRAL  PRINCIPLES. 

General ;   digitalis,  strophanthus,  squill,  salicin,  cantharidin,  thiosinamine, 

lecethin,  glycerophosphates      ........     283 


SECTION   XL— OTHER   SUBSTANCES   OF 
INTEREST. 

Pituitary  and  thyroid  extracts,  thyroxin,  vitamines,  saccharin     .          .         .     302 


ILLUSTRATIONS 


FIG.  PAGE 

1.  Ether  Production  and  Rectification  Plant          .....       10 

2.  Section  of  Fractionating  Column    .         .         .         .         .          .         .11 

3.  Rectifier  for  Ether  Purification        .......       14 

4.  Production  of  Chloroform  from  Alcohol  .          .          .         .         .          .       21 

5.  Chloroform  Manufacture  from  Acetone    ......       24 

6.  Washer  for  Chloroform  Purification 25 

7.  Sectional  Sketch  of  Chlorinating  Vessel  ......       26 

8.  Extraction  Plant — Fischer  Type ..50 

9.  Extraction  of  Aqueous  Liquids  with  Light  Solvents  .         .          .         -Si 

10.  Reaction  Vessel  for  Alkylation         .....         k         .       67 

11.  Vacuum  Still,  Oil-jacketed     .         .          .          .         .         .         .         •       73 

12.  Steam-heated  Ball  Mill  ...                                                        75 

13.  Lead-coated  Washer      .........       76 

14.  Vacuum  Still  for  Methyl-ecgonine  .          .          .         .         .  .94 

15.  Vacuum  Still  with  Stirrer  for  Phenetidine         .....     120 

16.  Benzoic  Acid  Sublimer 132 

17.  Vacuum  Dryer  for  Sodium  phenate  ......     134 

1 8.  Vacuum  Dryer  and  Carbonator        .         .         .          .         .         .  135 

19.  High-pressure  Autoclave  for  Carbonating         .          .         .          .         .136 

20.  Horizontal  M.S.  Steam -jacketed  Agitator 137 

21.  Enamelled  Still 152 

22.  Formaldehyde  Plant      .........     186 

23.  Vacuum  Still  for  Concentration  of  Extracts      .....     200 

24.  Film  Evaporator  ..........     234 


ziii 


ORGANIC    MEDICINAL 
CHEMICALS 

INTRODUCTION 

IN  the  thirteenth  century  Roger  Bacon  wrote  in  his  treatise, 
"  Of  the  Secret  Works  of  Art  and  Nature,"  that  "  a  person 
who  is  perfectly  acquainted  with  the  manner  which 
Nature  observes  in  her  operations  will  be  able  not  only  to 
rival  but  to  surpass  her. ' '  In  another  place  in  his  writings  we 
read  :  "  By  a  dexterous  application  of  the  knowledge  of 
the  properties  of  bodies  and  the  methods  of  Nature  many 
things  may  be  produced  more  surprising  than  all  the  pre- 
tended magic  has  ever  effected."  It  was  some  six  centuries 
after  Roger  Bacon  had  written  this  that  Wohler  first  built 
up  urea  in  the  laboratory  and  so  prepared  artificially  a  sub- 
stance identical  with  that  produced  in  nature.  During  the 
century  which  has  elapsed  since  that  achievement  chemists 
have  not  only  succeeded  in  rivalling  the  medicinal  agents 
produced  by  nature,  but  have  been  able  vastly  to  improve 
upon  them.  As  a  result  the  ordinary  practice  of  medicine 
to-day  is  to  a  large  extent  dependent  upon  the  products  of 
synthetic  chemistry.  Roger  Bacon's  remarkable  prophecy 
that  discovery  would  come  from  a  study  of  the  methods  of 
Nature  has  been  strangely  verified  in  this  field  of  research. 
The  discovery  of  many  substances  of  use  in  medicine,  as, 
for  instance,  antipyrine,  eucaine,  homatropine,  epinine,  and 
aspirin,  was  the  direct  result  of  attempts,  based  on  a  know- 
ledge of  the  chemical  constitution  of  natural  substances,  to 
improve  upon  them  or  to  cheapen  them.  It  is  true,  never- 
theless, that  chance  discovery  has  revealed  valuable  physio- 
logical properties  of  many  of  the  synthetic  compounds  which 
i.  i 


2  ORGANIC  MEDICINAL   CHEMICALS 

are  ni>w  of  great  iniDortance  in  medicine  ;  for  instance,  the 
purgative  actioii  of'  phenoiphthalein  was  accidentally  dis- 
covered from  its  employment  in  "  ear-marking  "  wines, 
and  the  antipyretic  properties  of  acetanilide  were  revealed 
hrough  the  action  of  a  laboratory  boy  in  mistaking  it  for 
ttaphthalene — a  discovery  which  led  to  that  of  other  and 
better  antipyretics.  Chance  discovery  may  in  the  future  dis- 
close valuable  physiological  properties  possessed  by  some  of 
the  many  thousands  of  organic  compounds  which  have  been 
prepared  during  the  past  fifty  years.  But  just  as  the 
discovery  of  these  numerous  substances  has  resulted  from 
earnest  attempts  to  extend  and  perfect  our  theoretical 
conceptions  of  chemical  constitution  and  change,  so  also  will 
most  of  the  future  discoveries  in  medicinal  chemistry  result 
from  a  study  of  body  metabolism  and  pathological  change 
in  health  and  disease.  Our  perfect  pharmacopoeia  can  only 
evolve  as  we  make  progress  in  knowledge  of  the  correlation 
between  chemical  constitution,  physical  properties,  and 
physiological  action.  The  theoretical  concepts  of  the 
nature  of  physiological  processes  are  as  yet  in  the  making, 
but  in  the  past  two  decades  such  progress  has  been  made  as 
to  give  confident  expectation  for  the  future. 

There  is  a  very  long  road  for  both  chemists  and  physio- 
logists to  traverse  before  they  can  set  up  reasonable  working 
hypotheses.  It  may  be  necessary  first  that  chemists  and 
mathematicians  should  succeed  in  deducing  from  chemical 
constitution  the  exact  physical  properties  of  a  substance. 
Certainly,  if  that  consummation  were  reached  the  pharma- 
cologist would  be  in  a  better  position  to  unravel  the  mysteries 
of  physiological  action.  For  the  present  it  may  be  said  of 
our  knowledge  that  it  shows  enough  remarkable  cases  of 
relationship  between  chemical  constitution  and  physiological 
action  to  encourage  and  assist  the  chemist  in  his  search  for 
new  and  useful  drugs,  and  to  suggest  the  importance  of  his 
working  in  close  association  with  the  pharmacologist. 

A  practically  useful  result  from  an  attempt  to  improve 
on  the  naturally  occurring  cocaine  is  the  synthesis  of  alpha- 
and  beta-eucaine,  both  of  which  possess  valuable  local 


INTRODUCTION  3 

anaesthetic  action  similar  to  that  possessed  by  cocaine. 
Cocaine  has  been  shown  to  possess  the  following  constitu- 
tion : 

CH2— CH CHCOOCH3 

I      I 
NCH3  CHOCOC6H5 

CH2— CH CH2 

The  preparation  of  substances  with  like  grouping  led  to  the 
production  of  alpha-eucaine,  but  this  was  found  unfortunately 
to  exercise  greater  irritating  effect  on  the  tissues.  Further 
research  revealed  the  substance  known  asbeta-eucaine,  which 
is  less  irritant  than  alpha-eucaine  and  less  toxic  than  cocaine 
itself,  and  consequently  preferable  to  the  latter.  The  simi- 
larity between  the  constitution  of  alpha-  and  beta-eucaines 
and  that  of  cocaine  is  clearly  shown  from  their  formulae  : 

(CH3)2-C CH2  (CH3)2— C CH2 

OOOOTT 
N-CH3     C<OCOC6l|g  NH    CHOCOC6H5 

(CH3)2— C CH2  CH3— CH— CH2 

-Bucaine.  ^^^-Eucaine. 

Beta-eucaine  is  now  commonly  employed  to  replace  cocaine, 
to  which  it  is  in  many  respects  preferable. 

A  classic  example  of  modern  research  for  therapeutic 
remedies  is  that  for  means  of  combating  diseases  such  as 
sleeping  sickness  and  syphilis,  which  are  caused  by  the 
presence  of  protozoan  parasites  in  the  blood  and  tissues. 
The  most  successful  of  the  remedies  which  have  been  dis- 
covered as  the  result  of  this  work  are  the  organic  arsenic 
compounds. 

In  the  course  of  research  inorganic  arsenic  compounds 
were  found  readily  to  destroy  such  parasites  in  vitro,  but 
only  under  conditions  which  were  found  to  be  also  destructive 
to  the  host.  Bhrlich  and  his  colleagues,  with  well-known 
success,  directed  researches  with  the  object  of  discovering 
derivatives  which  would  be  destructive  to  the  parasite  and 


4  ORGANIC   MEDICINAL  CHEMICALS 

harmless  to  the  host.  Their  work  was  rendered  additionally 
complicated  by  the  fact  that  surviving  organisms  which 
have  been  subjected  to  these  parasiticides  acquire  some 
degree  of  immunity  in  succeeding  generations. 

Atoxyl,  sodium-arsanilate 

ONa 
As^O 

XOH 

was  the  first  substance  introduced  for  this  purpose.  It 
was  found  to  be  very  effective  for  the  treatment  of  sleeping 
sickness,  but  the  frequent  cases  of  blindness  which  resulted 
from  its  use  made  necessary  the  search  for  other  and  better 
medicaments. 

Ehrlich  showed  that  atoxyl  exercised  much  greater 
influence  in  vivo  than  in  vitro,  and  from  the  known  reducing 
action  of  the  body  tissues  he  was  led  to  postulate  the  view 
that  this  difference  is  due  to  the  formation  within  the 
organism  of  trivalent  arsenic  derivatives,  by  reduction  of  the 
pentavalent  arsenic  in  atoxyl.  This  led  to  a  search  among 
trivalent  organic  arsenic  compounds  for  one  which  is  directly 
toxic  to  the  parasites,  as  arsenious  acid  is,  and  yet  possesses 
the  low  toxicity  to  the  host  exhibited  by  atoxyl. 

Finding  that  certain  dyes  possessed  parasiticidal  pro- 
perties and  at  the  same  time  selectively  stained  the  living 
protozoa,  he  therefore  supposed  that  it  might  be  possible 
to  find  an  arsenic  compound  which  in  analogy  with  these 
dyes  would  attach  itself  to  the  parasites  and  not  to  the 
tissues  of  the  host.  A  careful  technique  of  testing  his 
synthetic  compounds  both  in  vitro  and  in  living  rats  and 
mice  was  set  up,  and  a  very  large  number  of  substances 
were  thus  submitted  to  test,  especially  dyes  and  new  organic 
compounds.  In  this  manner  Ehrlich  was  finally  led  to 
select  salvarsan  and  neosalvarsan  as  the  remedies  most  nearly 
approaching  the  ideal. 

As  =  As  As  =  As 


H2N\X       \/NH2     H2NV       V— NH— CH2— S02Na 
OH       OH  OH       OH 

Salvarsan.  Neosalvarsan. 


INTRODUCTION  5 

This  choice  was  not  made  until  a  very  large  number  of 
substances  had  been  tested.  Some  of  the  dyes  which  were 
thus  discovered  to  be  fatal  to  protozoan  parasites  are  now 
rinding  practical  application  in  medicine.  In  particular 
methylene  blue,  malachite  green,  trypan  red,  scarlet  red, 
and  acriflavine  are  being  employed.  Acriflavine  has  proved 
to  be  of  greater  value  for  the  destruction  of  bacteria  than 
for  that  of  protozoa,  and  has  been  most  successfully  employed 
in  the  treatment  of  gonorrhoea  as  well  as  in  surgery.  Thus 
is  being  introduced  a  new  and  important  type  of  medication 
with  dyes. 

The  advance  in  our  knowledge  of  the  chemical  consti- 
tution of  active  substances  secreted  by  the  body,  especially 
that  of  the  so-called  hormones,  secreted  by  the  ductless 
glands,  indicates  another  and  extremely  important  direction 
in  which  progress  may  confidently  be  looked  for.  So  far 
the  preparation  of  the  pure  active  hormones  has  been  accom- 
plished only  in  the  case  of  two  of  the  glands.  The  first  to  be 
discovered  was  adrenaline,  the  principle  of  the  suprarenal 
gland.  This  discovery  has  led  to  extended  researches  upon 
other  amines  which  have  a  like  action,  and  was  the  starting- 
point  of  a  most  important  chapter  of  bio-chemistry. 

Adrenaline:    OH<(^>CHOH— CH2NHCH3 :      is      now 
OH 

manufactured    synthetically  as   well    as  prepared  from  the 
suprarenal  glands  of  oxen  and  sheep.   Since  the  synthetically 
produced   racemic  compound  is  less  active  than  its  Icevo. 
constituent  it  is  resolved  on  a  manufacturing  scale  and  the 
more  active  stereo-isomeride  employed. 

In  their  researches  on  amines  allied  to  adrenaline,  Barger 
and  Dale  have  shown  that  physiological  properties  some- 
what similar  to  those  of  adrenaline  are  exhibited  by  the 
amines  derived  by  loss  of  CO2  from  certain  amino  acids, 
such  as  tyrosine  and  leucine,  and  that  this  type  of  activity 
is  shown  in  varying  degrees  by  a  series  of  amines  intermediate 
in  structure  between  them  and  adrenaline.  The  greatest 
activity  is  possessed  by  those  having  two  phenolic  hydroxyl 


6  ORGANIC   MEDICINAL   CHEMICALS 

groupings  in  the  3-4  position  relative  to  a  side  chain  consist- 
ing of  two  carbon  atoms  and  bearing  the  amino  group.  Also 
of  importance  amongst  substances  of  this  type  is  histamine, 
beta-iminazolyl-ethylamine,  which  has  a  very  powerful 
physiological  action  of  a  different  type. 

NH— 

—  CH2—  NH2 


This  base  is  derived  from  histidine,  which  is  an  amino  acid, 
by  the  loss  of  CO2.  Histamine  has  become  of  great  interest 
in  bio-chemistry  and  it  has  been  recently  suggested  that  it 
is  one  of  the  active  constituents  of  the  pituitary  gland.  It 
results  from  the  putrefaction  of  animal  tissues  and  is  also 
present  in  extract  of  ergot.  Since  histidine,  from  which  it 
is  derived,  is  a  constituent  part  of  most  body  proteins,  its 
production  in  minute  quantity  by  biochemical  change  is  not 
inconceivable.  I^ike  adrenaline  it  is  now  manufactured 
synthetically. 

A  more  recent  discovery  is  thyroxin,  the  hormone  of 
the  thyroid  gland.  The  value  of  this  gland  in  therapeutics 
has  been  known  since  1891,  but  not  till  the  year  1917  was 
the  isolation  of  the  active  principle  by  Kendall  reported. 
Not  only  has  the  purified  crystalline  substance  been  rendered 
available  for  therapeutic  use,  but  its  constitution  has  been 
determined.  Kendall  states  it  to  be  a  tri-hydro-tri-iodo- 
hydro-j3-indole-propionic  acid,  and  assigns  to  it  the  following 
formula  : 

IH 

=,C—  CH2-~CH2COOH 


H   NH 

It  is  related  to  tryptophane,  an  amino  acid,  produced  by  the 
hydrolysis  of  proteins,  which  seems  to  play  a  special  and 
peculiar  part  in  nutriment,  its  absence  from  the  diet  having 
been  found  to  be  accompanied  by  loss  of  weight  and 
ultimate  death.  This  is  significant  when  we  bear  in  mind 
the  remarkable  effects  on  metabolism  produced  by  thyroxin 


INTRODUCTION  7 

itself.  The  latter  in  small  doses  exercises  a  remarkable 
influence  upon  the  rate  of  body  metabolism,  which  rate  is 
of  fundamental  importance  in  all  bio-chemical  change.  There 
seems,  therefore,  hardly  any  finality  to  the  power  over  the 
body  mechanism  which  may  be  acquired  by  the  aid  of 
chemistry.  In  this  connection  it  is  the  chemist's  object  to 
place  in  the  hands  of  those  who  practise  medicine  the  most 
perfect  armoury  for  their  combat  with  disease.  What  has 
been  achieved  so  far  must  be  regarded  as  merely  indicating 
the  road. 


SECTION  I.— NARCOTICS  AND  GENERAL 
ANESTHETICS 

THE  following  chapter  deals  with  the  method  of  preparation 
of  the  principal  synthetic  substances  which  have  found 
general  use  in  medicine  for  their  action  upon  the  central 
nervous  system. 

In  every  case  the  practical  requirement  is  either  that  of 
a  sedative  or  the  promotion  of  sleep,  whether  it  be  of  a 
temporary  character  as  in  the  case  of  volatile  anaesthetics 
such  as  ether  or  chloroform,  or  of  a  more  lasting  character 
such  as  the  sleep  produced  by  veronal.  From  remote  times 
opium  and  alcohol  have  been  used  for  this  purpose,  and  while 
both  are  retained  for  use  in  medicine,  they  have  been  largely 
supplanted  by  later  discoveries  of  chemical  substances 
possessing  less  disadvantages  than  those  of  opium  and 
alcohol. 

Most  of  these  substances,  however,  exert  other  actions 
besides  that  on  the  central  nervous  system,  and  the  search 
for  the  ideal  narcotic  which  is  free  from  any  by-effects 
must  still  be  continued.  Many  interesting  theories  relating 
to  narcotic  action  have  been  advanced,  but  no  satisfactory 
generalisation  has  been  adduced  as  to  the  nature  of  the 
chemical  groupings  which  bring  about  the  change  in  the 
circulation  of  blood  in  the  brain  that  results  in  sleep. 

Substances  containing  ethyl  groups  are  generally  more 
narcotic  than  those  containing  methyl,  and  less  depressant 
than  those  containing  higher  alkyl  groupings.  The  sub- 
stitution of  hydrogen  by  halogen,  especially  chlorine,  increases 
the  action  in  many  instances - 

8 


NARCOTICS  AND  GENERAL   ANESTHETICS     9 

ETHER— ethy lie  ether,  sulphuric  ether,  C2H6 .0.C2H6 .  74. 
— Ether  is  made  by  the  dehydration  of  alcohol  with  sulphuric 
acid.  The  technique  of  this  method  has  been  well  developed 
by  the  Explosives  Department,  Ministry  of  Munitions, 
through  whose  courtesy  we  are  enabled  to  give  an  account, 
necessarily  abbreviated,  of  the  process  for  manufacturing 
ether  as  carried  out  at  H.M.  factories,  Pembrey  and  Gretna. 

The  plant,  which  has  a  productive  capacity  of  25  tons  of 
ether  per  24  hours,  is  largely  covered  by  the  patents  of 
Barbet,  to  whom  the  illustrations  given  are  to  be  attributed. 
The  process  is  smooth  running  and  continuous,  and  in  essence 
consists  of  passing  ethyl  alcohol  vapour  through  a  heated 
mixture  of  sulphuric  acid  and  ethyl  sulphuric,  or  sulphonic, 
acid,  C2H6HSO4,  whereby  the  elements  of  water  are  ab- 
stracted. 

C2H5  .OH  +H2S04 =C2H6HS04  +H2O 

C2H5HS04+C2H6OHH»  (C2H5)20+H2S04 

The  issuing  vapours,  consisting  of  ether,  alcohol,  and  water, 
are  separated  into  their  constituents,  by  means  of  very 
carefully  designed  fractionating  and  analysing  columns. 

During  a  period  in  which  over  5000  tons  of  ether  were 
produced,  the  efficiency  of  the  process  averaged  94-3  %, 
100  tons  of  ether  requiring  131*2  tons  of  100  %  alcohol 
(142-6  tons  of  92  %  alcohol) ;  124*3  tons  of  100  %  alcohol 
being  required  according  to  theory. 

The  plant,  which  is  by  Barbet,  is  illustrated  in  Figs, 
i  and  2.  The  still,  or  reaction  vessel,  is  constructed  of  mild 
steel  plates  and  is  lined  with  lead.  It  is  9  ft.  2  ins.  diameter 
by  ii  ft.  6  ins.,  is  insulated  and  contains  a  steam  coil  of 
ij  ins.  lead  piping  5  ft.  2  ins.  high  and  3  ft.  8  ins.  diameter, 
and  an  open  lead  coil  of  3  ins.  diameter  provided  with  }  in. 
holes  by  which  the  alcohol  vapour  is  admitted.  The  cover, 
of  copper  plate,  is  provided  with  (i)  an  inspection  hole  ; 
(2)  a  manhole  ;  (3)  a  vapour  outlet  pipe  6J  ins.  diameter  in 
a  copper  turret  provided  with  a  baffle  plate  ;  (4)  connection 
for  alcohol  vapour  pipe  ;  (5)  connections  for  steam  pipe  ;  (6) 
connections  for  acid  pipes  ;  (7)  thermometer  tube. 


10 


ORGANIC  MEDICINAL   CHEMISTRY 


The  fractionating  column  is  made  of  copper  and  consists 
of  eleven  sections  joined  and  bolted  together,  each  section, 


ETHER     CONDENSERS 


UNCONDENSABLC 
GASES    TO  AIR 


FIG.  i. — Ether  production  and  rectification  plant. — Barbet. 

with  the  exception  of  the  bottom  and  reducing  sections, 
fitted  into  trays  containing  calottes  and  drip  pipes.  A 
diagram  of  a  section  is  shown  in  Fig.  2.  The  reducing 


NARCOTICS   AND  GENERAL  ANAESTHETICS     n 


section  contains  a  tray  with  drip  pipes  only  and  divides 
the  column  into  two  parts. 

(a)  The  lower  part,  22  ft.  high  by  5  ft.  3  ins.  diameter, 
consists  of  22  trays  and  comprises  the  portion  of  the  column 
from  which  recovered  alcohol  is  drawn  off. 

(b)  The  upper  part,  7  ft.  4  ins.  high  by  4  ft.  10  ins.,  consists 
of  ii  trays  and  con- 

tains the  "  Ether 
Zone  "  from  which 
rectified  ether  is  with- 
drawn. 

In  the  reducing 
section  below  the 
plate  is  a  6J  ins. 
copper  pipe  for  con- 
veying vapours  to 
the  alcohol  condenser 
and  a  3^  ins.  copper 
pipe  for  conveying 
liquid  from  the 
alcohol  condenser. 
Above  the  plate  is 
a  6  J  ins.  copper  pipe 


for     conveying 
pours      from 


va- 
the 

alcohol  condenser  to 
the  upper  part  of  the 
column.  A  ins. 


— ^     ^ —  -— -^   •  IYI-- 


FIG.  2. — Section  of  fractionating  column. 


copper  pipe  leads  from  the  top  of  the  column  to  the  ether 
condensers,  and  a  i  J  ins.  pipe  with  cock  from  the  third  tray 
to  the  ether  cooler. 

The  three  condensers,  one  for  alcohol  and  two  for  ether, 
made  of  copper,  3  ft.  9  ins.  diameter  by  7  ft.  7  ins.  high,  are 
of  the  tubular,  water-cooled,  surface  type.  Each  contains 
492  tubes  of  1  1  ins.  external  diameter  by  about  6  ft.  long. 

The  vaporiser,  8  ft.  8  ins.  high  by  2  ft.  diameter,  is 
constructed  of  mild  steel  plates  and  is  built  in  two  sections. 
The  bottom  section  contains  151  steam-heated  mild  steel 


12  ORGANIC   MEDICINAL  CHEMICALS 

tubes,  f  in.  internal  diameter.  A  ij  ins.  alcohol  feed  pipe 
enters  this  section  near  the  bottom.  The  top  section 
contains  a  baffle  plate  and  is  fitted  with  a  cover  with  a  3  ins. 
outlet  pipe,  on  which  an  atmospheric  relief  pipe  is  provided. 
The  vaporiser  is  also  fitted  with  a  steam  pressure  gauge, 
steam  safety  valve,  gauge  glass,  and  thermometer  fittings. 
A  tee-piece  is  provided  on  the  outlet  pipe,  one  branch  leading 
through  a  3  ins.  lead  pipe  to  the  alcohol  feed  coil  in  the  still, 
the  other  to  the  fractionating  column. 

The  process. — With  one  part  by  volume  of  sulphuric 
acid  (78  %  by  weight)  are  mixed  two  parts  by  volume  of 
undeiiatured  alcohol  (92  %  by  weight),  and  2600  gallons  of 
the  mixture  are  pumped  into  the  still.  This  is  heated  up, 
and  at  the  same  time  steam  is  turned  on  to  the  alcohol 
vaporiser,  being  so  regulated  that  liquid  alcohol  does  not 
appear  in  the  gauge  glass.  When  the  temperature  in  the 
still  reaches  105°  a  small  supply  of  alcohol  vapour  is 
admitted,  and  this  quantity  is  gradually  increased  as  the 
temperature  rises.  When  at  121°,  the  steam  is  shut  off, 
the  heat  of  reaction  being  sufficient  to  take  the  tempera- 
ture to  128°  at  which  it  is  maintained  throughout.  The 
issuing  vapours,  consisting  of  ether,  50  %  by  volume,  alcohol 
30  %  by  volume,  and  water  20  %  by  volume,  are  bubbled 
through  a  2  %  solution  of  caustic  soda  in  the  scrubber,  and 
then  pass  to  the  fractionating  column,  entering  between  the 
ninth  and  tenth  trays  from  the  bottom.  The  lower  portion 
of  the  column  has  previously  been  heated,  and  at  the  time 
the  vapours  commence  to  pass  over,  the  trays  are  laden  with 
hot  water.  The  temperature  in  the  alcohol  condenser  is 
allowed  to  rise  to  50°  and  is  kept  at  this  by  regulation  of 
the  water  supply.  As  is  to  be  seen  from  the  diagram  of  a 
section  of  the  column,  the  vapours,  in  ascending  from  tray 
to  tray,  bubble  through  condensed  liquor.  Recovered  alcohol, 
containing  5  %  of  ether,  is  drawn  off  at  the  bottom  of  the 
eighth  section,  to  the  recovered  alcohol  cooler,  from  which 
it  is  pumped  up  to  the  alcohol  storage  tank  which  supplies 
the  vaporiser.  The  alkaline  scrubber  liquor,  which  contains 
some  alcohol,  is  passed  into  the  column  at  the  foot  of  the 


NARCOTICS  AND  GENERAL   ANESTHETICS     13 

fourth  section,  and  the  liquor  which  is  run  off  at  the  bottom 
of  the  fractionator  is  free  from  both  alcohol  and  ether. 

The  rectified  ether  is  withdrawn  from  the  "  ether  zone," 
at  the  third  tray  from  the  top  of  the  column,  and  runs 
through  the  cooler  to  a  storage  tank. 

A  certain  quantity  of  ether,  termed  the  "  heads,"  and 
containing  compounds  of  lower  boiling  point,  such  as  methyl 
ether,  and  dissolved  gases,  is  drawn  from  the  jacketed  tube 
connected  to  the  second  ether  condenser,  and  may  be 
collected  separately.  It  can  be  mixed  with  rectified  ether 
to-  form  Methylated  Ether  (s.g.  0717). 

The  quantities  of  materials  and  steam  consumed  per 
2240  Ibs.  of  ether  produced  are  as  follows  : — 

Alcohol  (92  %  ),  1*426  ton. 

Caustic  soda,  0*0014  ton. 

Sulphuric  acid  (100  %),  0*0012  ton. 

Water,  9000  gallons. 

Steam,  6000  Ibs.  using  fresh  alcohol ;  and  10,000  Ibs.  using 

recovered  liquors. 

Labour,  One  chargeman  and  4  labourers  for  20,000  gallons 
per  week. 

A  suitable  plant  for  rectifying  ether  is  illustrated  in  Fig.  3. 
The  ether  enters  through  a  preheating  coil  A  in  the  middle 
section  of  the  column  and  passes  by  the  drip  pipes  through 
the  lower  section  to  the  steam  coil. 

Ether  for  anaesthetic  purposes  is  required  (British 
Pharmacopoeia)  to  have  a  specific  gravity  of  0*720  to  0*722 
at  I5'5 °-  It  should  not  commence  to  distil  below  34*5° 
and  must  leave  no  residue  on  evaporation.  Ether  is  used  for 
producing  general  anaesthesia  by  inhalation  in  minor  surgical 
and  dental  operations.  It  has  a  less  depressing  action  than 
chloroform  upon  the  heart,  vessels,  and  respiratory  centre. 
When  taken  internally  it  acts  as  a  stimulant  and  carminative. 
So-called  methylated  ether  is  made  from  methylated  spirit. 
It  has  a  somewhat  lower  boiling  point,  due  to  the  presence  of 
methyl  ethyl  ether.  Methyl  ethyl  ether  is  superior  to  ethyl 
ether  when  employed  as  a  spray  for  producing  local  anaes- 
thesia in  minor  surgery.  For  this  purpose  ether,  however,  is 


14          ORGANIC  MEDICINAL   CHEMICALS 


1 

i 

DC 

fm 

, 

FIG.  3.— Rectifier  for  ether  purification. 


NARCOTICS   AND  GENERAL  ANESTHETICS    15 

less  efficient  than  ethyl  chloride,  besides  being  more  objec- 
tionable to  the  operator. 

Ether  is  a  valuable  solvent  and  is  employed  in  the 
manufacture  of  fine  chemicals,  for  which  purpose  pure  ethyl 
ether  is  to  be  preferred  to  methylated  ether. 


METHYLAL—  methylene  dimethyl  ether,  CH23  76.— 

\UL±i3 

Methylal  is  prepared  by  the  following  procedure  :  A  mixture 
of  2j  parts  of  methyl  alcohol,  containing  i  %  of  anhydrous 
hydrochloric  acid  and  i  part  of  paraformaldehyde,  is 
heated  under  a  reflux  condenser  at  40°-5o°  for  six  hours, 
and  then  allowed  to  stand  overnight.  The  acidity  is 
neutralised  by  the  addition  of  lime  and  the  mixture  is  then 
fractionally  distilled.  Methylal  is  a  colourless  volatile  liquid, 
s.g.  0-855,  B.P.  42°.  It  is  readily  soluble  in  water  and 
neutral  to  litmus.  Methylal  is  used  as  an  inhalation  anaes- 
thetic ;  also,  mixed  with  oil  or  glycerin,  as  a  local  anaesthetic. 
It  is  said  to  be  an  antidote  to  strychnine. 

PARALDEHYDE,  C6H12O3.  132.—  Paraldehyde  is  produced 
by  the  polymerisation  of  acetaldehyde.  Acetaldehyde  is  an 
intermediate  compound  in  the  manufacture  of  acetic  acid 
from  acetylene  or  ethyl  alcohol.  It  is  also  recoverable  from 
the  first  runnings  of  alcohol  distillation  in  the  fermentation 
industry.  Acetylene  is  to  be  regarded  as  the  chief  economic 
source  ;  from  it  acetaldehyde  is  prepared  by  passing  the  gas 
into  a  violently  agitated  suspension  of  mercuric  oxide  in 
sulphuric  acid.  The  process  has  been  the  subject  of  a  large 
number  of  patents.  A  useful  account  of  the  procedure  as 
carried  out  at  Shawinigan  Falls,  Quebec,  will  be  found 
in  the  Canadian  Chem.  J.  1919,  3,  258. 

The  polymerisation  of  acetaldehyde  is  conducted  as 
follows  :  500  Ibs.  of  acetaldehyde  are  placed  in  an  earthenware 
or  lead-lined  vessel  provided  with  a  stirrer  and  an  efficient  ice- 
or  brine-cooled  condenser.  One  cubic  centimetre  of  hydro- 
chloric acid,  s.g.  i'i8,  is  added.  After  a  time,  the  length  of 
which  is  dependent  upon  the  initial  temperature,  a  vigorous 
reaction  sets  in,  the  aldehyde  boiling  and  being  refluxed. 
When  this  slows  down  a  further  similar  quantity  of  acid  is 


16          ORGANIC  MEDICINAL  CHEMICALS 

added,  which  starts  the  reaction  afresh,  and  the  same 
procedure  is  repeated  until  no  further  heat  is  developed. 
The  maximum  degree  of  polymerisation  has  then  been 
attained,  and  the  liquid  is  neutralised  by  washing  with  water 
and  sodium  bicarbonate,  dried  with  anhydrous  potassium 
carbonate  and  fractionally  distilled,  a  very  efficient  rectifying 
and  analysing  column  being  required.  Unchanged  acetalde- 
hyde  passes  over  first  and  is  mixed  with  the  batch  next  to  be 
polymerised,  as  is  also  an  intermediate  fraction  which  consists 
of  a  mixture  of  aldehyde  and  par  aldehyde. 

The  fraction  distilling  at  123°-! 25°  consists  of  pure 
paraldehyde  ;  a  colourless  mobile  liquid,  having  a  charac- 
teristic odour,  and  neutral  in  reaction  towards  litmus.  B.P. 
124°,  M.P.  10°.  When  mixed  with  potassium  hydrate 
solution,  6  %,  no  colour  should  be  developed  within  two  hours. 

Paraldehyde  is  a  valuable  sedative  and  hypnotic.  It 
produces  quiet  and  refreshing  sleep  and  does  not  depress 
the  heart's  action.  It  is  largely  used  in  the  insomnia  of 
mania,  melancholia  and  other  mental,  and  also  cardiac, 
diseases.  It  has  a  marked  action  on  the  kidneys,  increasing 
the  flow  of  urine. 

ACETOPHENONE  or  Hypnone  —  phenyl  methyl  ketone, 
C6H5COCH3.  120. — Acetophenone  is  prepared  (see  Ber.  30, 
1769  [1897])  by  the  following  method  : 

C6H6+CH3COC1  ->  C6H5COCH3+HC1 

78  78-4  120  36-4 

Two  parts  of  sublimed  aluminium  chloride  powder  are 
covered  with  i'6  parts  of  dry  carbon  bisulphide  in  a  jacketed 
iron  still  provided  with  a  stirrer  and  a  reflux  condenser. 
Cold  brine  is  circulated  through  the  jacket  and  the  mixture 
stirred,  whilst  a  mixture  of  1*3  parts  of  acetyl  chloride  and 
i  *5  parts  of  dry  thiophene-free  benzol  is  added  slowly,  through 
a  pipe  reaching  below  the  level  of  the  liquid.  A  vigorous 
reaction  ensues,  and  is  kept  under  control  by  regulating  the 
rate  of  flow  of  the  mixture.  When  all  has  been  added  and 
the  evolution  of  gaseous  hydrochloric  acid  has  slowed  down, 
steam  is  passed  into  the  jacket  in  place  of  the  brine,  and  the 


NARCOTICS  AND  GENERAL  ANAESTHETICS    17 

mixture  boiled  for  half  an  hour.  It  is  then  cooled  and  run 
out  on  to  a  stirred  mixture  of  crushed  ice  and  water.  The 
lower  layer  consists  of  acetophenone  dissolved  in  carbon 
disulphide.  It  is  separated,  washed  free  from  acid,  dried, 
the  solvent  removed  and  the  acetophenone  purified  by 
distillation  in  vacuo. 

Acetophenone  forms  colourless  crystals,  m.p.  20°.  The 
commercial  product  is  often  a  liquid.  It  boils  at  201°,  is 
insoluble  in  water,  but  readily  dissolved  by  alcohol. 

Ivike  many  other  ke tones  it  possesses  fairly  strong 
hypnotic  properties.  Its  homologue  phenylethyl  ketone  has 
a  more  powerful  action,  but  is  not  commonly  employed. 
The  ure thanes  and  sulphones  (see  pp.  32-48)  are  generally 
regarded  as  safer  hypnotics  for  general  use. 

ETHYL  CHLORIDE  —  KELENE  —  C2H6C1.  64-4.  —  Two 
methods  are  in  use  for  the  manufacture  of  ethyl  chloride,  one 
(the  older)  involving  the  use  of  a  high-pressure  lead-lined 
autoclave.  The  descriptions  that  follow  are  based  on  those 
given  in  Ullmann's  Encyclopedia  der  Technischen  Chemie. 

(1)  Molecular  quantities  of  94  %  alcohol  and  hydrochloric 
acid  (sp.gr.  i'i6,  or  higher  gravity  if  available)  are  mixed 
in   a  jacketed  autoclave  homogeneously  lined   with   lead. 
Heat  is  applied,  the  temperature  being  raised  slowly,  in  the 
course  of  3  hours,   to  120°,  at  which  it  is  maintained  for 
a  further  2-4  hours,  that  is,  until  the  pressure  no  longer 
increases.     The  reaction  mixture  is  then  cooled  to  60°  and 
the  vapours  are  led  through  towers  in  which  they  are  washed 
successively  with  water,  caustic  soda  solution,  and  concen- 
trated sulphuric  acid.     The  ethyl  chloride  is  finally  con- 
densed in  an  earthenware  coil  cooled  to  — 10°  by  means 
of  circulating  cold  brine,  and  led  into  a  jacketed  and  cooled 
receiver. 

(2)  Seventy-five  parts  by  weight  of  alcohol,  200  parts  of 
hydrochloric  acid  (sp.gr.  i'i6,  or  higher  gravity  if  available), 
and  64  parts  of  calcium  chloride  are  added  to  200  parts  of 
the  residue,  adjusted  to  sp.gr.  1*208,  of  a  previous  operation, 
such  residue  being  contained  in  an  earthenware  still  set  in  a 
water  bath.     The  still  is  provided  with  a  vertical  outlet  pipe, 

i.  2 


i8  ORGANIC  MEDICINAL  CHEMICALS 

which  condenses  and  returns  the  unchanged  alcohol  vapour. 
The  ethyl  chloride  vapours  pass  through  a  series  of  wash 
towers,  successively  containing  water,  acid  sodium  bichromate 
solution,  caustic  soda,  and  concentrated  sulphuric  acid, 
and  condensed  in  a  brine-cooled  earthenware  coil.  The 
whole  system  is  maintained  under  a  slight  positive  pressure 
during  operation. 

Heat  is  applied  slowly,  the  temperature  being  raised 
until  ethyl  chloride  is  seen,  through  a  suitably  placed  sight 
glass,  to  be  evolved.  The  distillation  is  so  conducted  that 
a  regular  flow  of  distillate  is  secured,  the  operation  taking 
8-9  hours,  in  which  time  70-72  parts  of  ethyl  chloride  are 
obtained. 

Of  the  residue  in  the  still  200  parts  are  left  for  the  next 
operation,  the  gravity  being  adjusted  to  1*208  by  addition 
of  water.  The  remainder  is  neutralised  with  lime  and  the 
calciurn  chloride  recovered  by  evaporation. 

Bthyl  chloride  is  a  neutral,  colourless,  volatile,  inflam- 
mable liquid  distilling  at  12*5°  and  having  a  sp.gr.  at  o° 
of  0*921.  lyatent  heat  of  vaporisation  100.  It  may  safely 
be  stored  in  metal  vessels  able  to  withstand  a  gauge  pressure 
of  15  Ibs.  per  sq.  in. 

It  is  employed  as  an  ethylating  agent  in  synthetic 
processes.  In  medicine  it  is  used  for  producing  local 
anaesthesia.  Its  effectiveness  for  this  purpose  results  from 
its  action  as  a  refrigerant,  due  to  its  low  boiling-point.  It 
is  also  employed  as  a  general  inhaled  anaesthetic  for  minor 
operations,  being  quick  in  its  action  and  leaving  no  after 
effects.  In  point  of  safety  it  is  said  to  stand  between  ether 
and  chloroform. 

Small  quantities  of  ethyl  chloride  present  in  chloroform 
are  believed  to  improve  the  anaesthetic  qualities  of  the  latter. 
When  made  from  methylated  alcohol,  ethyl  chloride  contains 
methyl  chloride  unless  separated  therefrom  by  careful 
fractionation. 

ETHYL  BROMIDE  C2H5Br.  109.— The  following  method, 
based  on  that  given  by  Weston  (Trans.  J.  C.  S.  1915,  107, 
1489),  is  satisfactory  and  economical. 


NARCOTICS  AND  GENERAL  ANESTHETICS    19 

Twenty  parts  of  ice  are  added  to  625  parts  of  sulphuric 
acid  (sp.gr.  1*84)  contained  in  a  jacketed  enamelled  or  lead- 
lined  still  provided  with  a  stirrer,  and  fitted  to  a  condenser  ; 
after  cooling  this  mixture,  276  parts  of  absolute  alcohol  are 
added.  During  addition  of  the  alcohol  the  mixture  is  well 
stirred  and  the  temperature  kept  below  40°.  The  mixture 
is  allowed  to  stand  overnight,  after  which  are  added  618 
parts  of  coarsely  powdered  anhydrous  sodium  bromide. 
The  stirring  is  now  started  and  steam  admitted  cautiously 
to  the  jacket.  The  temperature  is  raised  slowly  and  steadily 
until  ethyl  bromide  commences  to  distil.  The  distillation 
is  conducted  gently,  the  temperature  being  increased  only 
when  the  flow  of  ethyl  bromide  from  the  condenser  slows 
down.  Attached  to  the  end  of  the  condenser  is  an  adaptor 
dipping  below  the  surface  of  a  layer  of  water  which  is  kept 
in  the  receiver.  No  frothing  occurs  if  the  heating  is  carefully 
conducted.  When  the  evolution  of  ethyl  bromide  Ijas  ceased, 
sodium  carbonate  is  added  to  the  liquid  in  the  receiver  until 
the  mixture  is  slightly  alkaline  after  agitation.  The  aqueous 
layer  is  then  separated  from  the  heavier  layer  of  ethyl  bromide 
and  evaporated  down,  when  a  quantity  of  sodium  bromide  is 
recovered.  The  ethyl  bromide  layer  is  washed,  once  by 
churning  with  water  in  a  lead-lined  agitator,  and  then  with 
successive  quantities  of  concentrated  sulphuric  acid,  until 
the  acid  is  no  longer  coloured,  and  until  the  specific  gravity 
at  15 -5°  exceeds  1-45.  The  sulphuric  acid  is  used,  with  the 
exception  of  the  first  washing,  for  making  up  the  reaction 
mixture  for  a  succeeding  batch. 

The  product  is  finally  rectified  in  earthenware,  enamelled, 
or  silica  apparatus.  Yield,  550-560  parts. 

Ethyl  bromide  is  a  colourless,  inflammable,  strongly 
refractive  liquid  having  a  pleasant  ethereal  odour.  B.p. 
38°-39°;  sp.gr.  i -453-1 -457/15°. 

It  is  a  local  and  general  anaesthetic,  similar  to  chloro- 
form, but  more  rapid  in  its  action,  and  is  occasionally  used  in 
conjunction  with  it.  It  produces  anaesthesia  rapidly  and 
is  useful  in  minor  surgery  and  in  dental  operations.  In 
inexperienced  hands,  however,  ethyl  bromide  must  be 


20  ORGANIC  MEDICINAL  CHEMICALS 

regarded  as  a  dangerous  agent,  as  the  respiration  is  paralysed 
at  about  the  same  time  as  the  reflexes,  so  that  the  zone  of 
safety  is  very  narrow. 

CHLOROFORM  CHC13.  119-4.— For  the  manufacture  of 
chloroform  there  are  many  methods  of  industrial  importance. 
Chief  among  them  are  those  in  which  bleaching  powder 
reacts  with  alcohol  or  acetone  ;  but  in  addition  to  these, 
chloroform  is  made  through  chloral  hydrate  prepared  from 
chlorine  and  alcohol.  It  is  also  made  by  an  electrolytic 
process  and  by  the  reduction  of  carbon  tetrachloride. 

Manufacture  from  Alcohol. — The  best  published  descrip- 
tion of  the  method  of  manufacturing  chloroform  from 
alcohol  and  bleaching  powder  is  that  given  by  Frerichs 
(/.  Ind.  <§•  Eng.  Chem.,  1912,  iv.  345  and  406).  He  describes 
the  process  as  it  was  being  carried  out  in  an  American 
factory,  and  as  it  was  modified  as  the  result  of  his  own 
experimental  work. 

By  the  original  process  for  making  100  parts  of  pure 
chloroform  1440  parts  of  35  %  bleaching  powder,  and 
72-73  parts  of  100  %  alcohol  were  consumed.  By  the 
modified  method  the  corresponding  figures  were  977  parts 
°f  33 '3  %  bleaching  powder  and  69-5  parts  of  100  %  alcohol. 
The  essential  difference  between  the  two  methods  is  that 
whereas  as  originally  carried  out  the  whole  of  the  bleaching 
powder  was  mixed  with  the  aqueous  alcohol  before  the  heat- 
ing was  commenced,  by  the  modified  process  the  bleaching 
powder  was  added  gradually  to  the  hot  dilute  alcohol.  This 
modification  was  based  on  the  observation  that  the  yield 
of  chloroform  obtained  by  heating  chloral  hydrate,  which 
may  be  assumed  to  be  an  intermediate  in  the  formation  of 
chloroform  from  alcohol  with  lime,  is  greatest  if  the  materials 
are  mixed  at  the  boiling-point  of  their  aqueous  solutions. 

2C2HftOH+8Ca(OCl)2  ->  2CCl3CHO+3Ca(OH)2+5CaCla+H2O 
92  I3°3  4/ 

2CHCl3+Ca(HCOO)2+2Ca(OH)2+5CaCl2+2H20 
239 

A  general  design  of  the  plant  is  illustrated  in  Fig.  4. 
The  vessels  A  and  B  are  constructed  of  wrought  or 


NARCOTICS  AND  GENERAL  ANESTHETICS    21 

cast-iron,   the  condenser  of  copper  and    the    receivers  of 
galvanised  iron. 

Ninety-six  gallons  of  alcohol  (94  %  w/v)  are  diluted  with 
360  gallons  of  water  in  the  reaction  vessel  B.  The  equiva- 
lent of  1500  Ibs.  of  bleaching  powder,  35  %,  is  charged  into 
the  agitator  A  and  stirred  with  750  gallons  of  water.  The 
diluted  alcohol  is  then  heated  to  boiling  by  direct  steam, 


FIG.  4. — Production  of  chloroform  from  alcohol. 

and  the  bleaching  powder  mixture  added  gradually,  at 
such  a  rate  that,  without  further  addition  of  heat,  a  steady 
stream  of  chloroform,  which  is  mixed  with  some  alcohol, 
distils  over.  When  all  the  bleaching  powder  has  been  added, 
distillation  is  continued,  about  480  gallons  of  diluted  alcohol 
being  obtained,  in  addition  to  the  chloroform,  in  each 
operation. 

This  480  gallons  of  dilute  alcohol  is  used,  together  with 


22 


ORGANIC  MEDICINAL  CHEMICALS 


fresh  alcohol,  to  produce  a  further  quantity  of  20  %  alcohol 
for  making  up  the  charge  for  the  second  operation,  which 
is  carried  out  in  exactly  the  same  way. 

The  following  are  the  results  given  for  a  series  of  six 
operations  carried  out  as  above  : — 


Operation. 

Bleaching  powder. 

Eng.  gallons 
alcohol 
94%. 

Chloroform, 
s.g.  r48. 

Weight. 

Per  cent. 
Cl. 

Equal  to  Ibs.  at 
35%. 

I 

1694 

31 

1500 

96 

125 

2 

1694 

31 

1500 

12 

H7 

3 

1694 

31 

1500 

12 

159 

4 

1694 

31 

1500 

12 

158 

5 

1694 

31 

1500 

12 

153 

6 

1694 

31 

1500 

12 

159 

Not  counting  the  first  two  days,  in  which  the  previous 
charges  have  no  influence  upon  the  yield,  the  average 
consumption,  for  making  100  Ibs.  of  chloroform  was  952  Ibs. 
°f  35  %  bleaching  powder.  A  record  of  a  thirty-three 
days'  run  with  6  units  of  plant  showed  a  yield  of  30,675  Ibs. 
of  pure  chloroform. from  299,525  Ibs.  of  35  %  bleaching 
powder  and  2753  gallons  of  94  %  alcohol. 

The  amount  of  steam  consumed  was  2  tons  for  100  Ibs. 
of  chloroform  produced.1 

Manufacture  from  Acetone. — Bleaching  powder  (35  %), 
1400  Ibs.,  is  mixed  with  700  gallons  of  water  in  an  iron 
mixer  fitted  with  rousing  gear,  and  the  mixture  is  trans- 
ferred to  an  iron  reaction  vessel  of  2000  gallons  capacity 
fitted  with  stirring  gear,  steam  and  water  inlets,  and 
connected  through  a  long  stillhead  to  an  effective  con- 
denser. The  sludge  is  kept  stirred  and  is  heated  to  45°, 
steam  then  being  shut  off.  Acetone,  122  Ibs.,  mixed 
with  an  equal  volume  of  water,  is  next  added,  in  the  course 
of  10-15  minutes.  The  heat  evolved  by  the  reaction  raises 
the  temperature  to  about  60°,  and  chloroform  distils  over. 
When  the  rate  of  evolution  commences  to  slow  down, 


1  Baskerville  and  Hamor,/.  Ind.  &  Eng.  Chem.,  iv.,  212,  278,  362,  422, 
499,  571. 

Dott,  /.  Soc.  Chem.   Ind,,  27,  6,  271. 


NARCOTICS  AND  GENERAL  ANAESTHETICS    23 

additional  heat  is  applied  and  the  distillation  carried  on 
until  the  condensate  no  longer  contains  oily  drops  of 
chloroform. 

The  plant  designed  by  Meyer  is  illustrated  in  Fig.  5.  In 
the  iron  mixer  A  the  bleach  and  water  are  mixed.  B  is 
the  reaction  vessel,  and  C  the  acetone  container.  D  is  a 
condenser,  B  a  washer  and  F  the  receiver. 

The  condensate  of  crude  chloroform  is  then  separated 
from  the  upper  layer  of  water,  and  set  aside  for  further 
purification.  The  aqueous  layer  is  returned  to  the  reaction 
vessel. 

The  above  quantities  yield  about  105  parts  of  crude 
chloroform.  The  yield  is  stated  in  UUmann's  Encyclop.  der 
Tech.  Chem.  to  be  100  parts  of  chloroform  from  600  parts 
°f  35  %  bleaching  powder  and  57  parts  of  acetone. 

The  relative  economic  advantage  of  using  one  or  other 
of  these  methods  depends,  of  course,  on  the  prices  of  bleach- 
ing powder,  acetone,  and  alcohol,  and  it  may  happen  that 
at  different  periods  or  in  different  countries  either  method 
may  be  the  cheaper. 

Manufacture  by  Electrolytic  Process  (Rev.  d.  Prod.  Chim. 
3>  3°9)- — A  20  %  solution  of  NaCl  is  heated  at  100°  in  a 
leaden  still  and  is  kept  agitated  by  means  of  carbon  spatulas 
which  at  the  same  time  serve  as  anodes  for  a  5-6  amp. 
current.  Acetone  is  introduced  into  the  bottom  of  the  still 
and  is  acted  upon  by  the  chlorine,  forming  a  compound — 
probably  trichloracetone — which  is  decomposed  by  the  action 
of  the  caustic  soda  produced,  giving  chloroform. 

The  yield  is  stated  to  be  85  %  of  the  theoretical. 

Manufacture  from  Carbon  Tetrachloride. — Chloroform  is 
also  manufactured  from  carbon  tetrachloride,  by  reducing 
this  with  iron  powder  and  weak  acid,  or  with  zinc  and 
hydrochloric  acid  (Chem.  Rev.  1896,  88),  but  it  may  be 
doubted  whether  a  product  of  pharmaceutical  quality  is  as 
yet  obtainable  from  this  source. 

Manufacture  from  Chlorinated  Alcohol  or  Chloral. — 
According  to  D.  R.  P.  129237,  chlorine  is  passed  into  cold 
stirred  alcohol  until  the  density  has  reached  1*32,  or  (J.  Chem. 


ORGANIC  MEDICINAL  CHEMICALS 


NARCOTICS  AND  GENERAL  ANESTHETICS    25 

Ind.  Tokyo,  1918,  21,  219)  until  the  two  layers  which  form 
are  almost  equal  in  volume.  One  hundred  parts  of  the 
chlorinated  product  are  added  to  a  mixture  of  500  parts 
of  bleaching  powder,  100  parts  of  slaked  lime,  and  2000 
parts  of  water.  Heat  is  applied,  and  the  chloroform  slowly 
distilled  over.  It  is  stated  that  95-98  parts  of  chloroform 
are  yielded  by  100  parts  of  alcohol. 

By  whichever  process  described  above  chloroform  is 
produced,  it  requires  '  considerable  further  treatment  to 
render  it  pure  enough  for  medicinal  purposes.  Absolute 
freedom  from  aldehyde,  ketone,  phosgene,  carbon  tetra- 
chloride  or  like  impurity  must  be  secured  by  agitating  it 
successively  with  sulphite  or  thiosulphate,  an  oxidising  agent 
such  as  bichromate,  sulphuric  acid  and  an  alkali.  A  suitable 


FIG.  6. — Washer  for  chloroform  purification. 

washer  is  shown  in  Fig.  6.  It  should  be  lead-coated  through- 
out. The  chloroform  is  finally  dried  and  distilled  by  careful 
fractionation  and  the  constant  boiling  fraction  is  alone 
employed. 

To  the  freshly  distilled  chloroform  the  amount  of  absolute 
alcohol  required  to  reduce  the  gravity  to  1*485-1 '487  must 
be  added  as  a  preservative. 

Pure  chloroform  may  be  produced  directly  from  pure 
chloral  hydrate  by  the  action  of  caustic  alkali. 

Chloroform  is  a  colourless,  refractive,  volatile  liquid, 
sp.gr.  1-4988,  but  as  commonly  sold  admixed  with  2  %  of 
alcohol,  1-485-1-487  ;  b.p.  61-2°.  It  must  withstand  the 
stringent  tests  of  the  B.P.  and  U.S. P.  if  employed  for 
pharmaceutical  purposes.  No  colour  should  be  given  when 
20  c.c.  are  shaken  with  15  c.c.  of  cone.  H2SO4  and  4  c.c.  of 


26 


ORGANIC  MEDICINAL  CHEMICALS 


40  %  formaldehyde.  In  order  to  make  it  withstand  this 
test  great  care  is  required  to  avoid  contamination  with  any 
organic  matter  such  as  cork  or  grease,  and  the  alcohol  em- 
ployed as  a  preservative  must  be  carefully  selected. 

CHLORAL  HYDRATE  CC13CH(OH)2.  165-4.— Until  the 
commencement  of  the  present  century  the  chlorination  of 
alcohol  to  chloral  hydrate  was  carried  out  in  glass  containers, 
in  which  25  kg.  of  absolute  alcohol  were  slowly  chlorinated, 


pour 

Liquor 
enter  and 
exit  pipe 


Glass  globes 
for  lamps 


V 


FIG.  7. — Sectional  sketch  of  chlorinating  vessel 

first  in  the  cold,  then  with  temperature  gradually  increasing 
to  90°-95°,  an  operation  taking  6-8  weeks,  day  and  night. 
This  procedure  was  naturally  very  costly,  and  necessitated 
much  labour  and  supervision. 

As  carried  out  by  D.  R.  P.  198422,  homogeneously  lead- 
lined  jacketed  vessels  of  200-500  litres  capacity,  coated 
internally  with  porcelain  tiles,  are  employed,  fitted  with 
stirring  gear,  a  jacket,  and  internal  coils,  through  which 
either  cold  brine,  water  or  steam  can  be  passed,  and  numerous 


NARCOTICS  AND  GENERAL  ANESTHETICS    27 

chlorine  distributing  tubes.  The  vessel  illustrated  (Fig.  7) 
is  suitable  for  chlorinations  generally.  It  is  fitted  with 
globes  for  electric  lamps,  employed  for  accelerating  the 
reaction.  The  vessel  is  filled  to  two-thirds  of  its  capacity 
with  alcohol.  liquid  chlorine  may  be  employed,  being  dis- 
tributed in  fine  drops.  The  apparatus  is  kept  under  slight 
pressure,  and  several  vessels  may  be  arranged  in  series,  so 
that  no  chlorine  is  lost.  The  operation  is  finished  in  3-5 
days  of  24  hours.  On  the  first  day  the  temperature  of  the 
alcohol  is  kept  at  20°-25° ;  and  it  is  slowly  raised  to  5o°-6o° 
during  the  second  day,  the  specific  gravity  after  48  hours 
being  35°-40°  Be.  Finally,  the  temperature  is  raised  to 
95°,  the  operation  usually  being  finished  when  the  specific 
gravity  reaches  49°  Be. 
Reactions : 

CH3CH2OH  ->  CH2C1— CHCl— OH  ->  CH2C1CHC1OC2H5 

CHC121:HC10C2H5  ->  CHC12CH<°*?  R  ->  CCl3CH<g*?  R 

Chloral  alcoholate  is  the  main  constituent  of  the  reaction 
mixture  at  the  end  of  the  operation  (A.  279,  293  ;  A.  ch. 
IO,  3320).  .  Volatile  chlorinated  by-products  containing 
ethyl  chloride  are  recovered  from  the  exit  vapours  by 
condensation  in  stoneware  towers. 

The  reaction  mixture  is  allowed  to  cool,  when  part  of 
the  chloral  alcoholate  crystallises  out.  An  equal  volume 
of  sulphuric  acid,  sp.  gr.  1*84,  is  added  in  the  cold,  and  the 
mixture  gradually  distilled.  Ethyl  chloride  distils  off  first, 
HC1  gas  being  also  evolved.  Between  70°  and  90°  ethyl 
alcohol  passes  over,  and  from  90°  chloral  commences  to 
distil. 

The  crude  chloral  is  neutralised  with  calcium  carbonate 
and  distilled  from  a  lead-lined  still,  the  vapours  passing 
through  a  heated  vessel  containing  lumps  of  limestone  before 
being  condensed. 

The  distilled  chloral  is  converted  into  chloral  hydrate 
by  the  gradual  addition,  with  cooling  and  stirring,  of  water, 
12 '2  parts  of  which  are  required  by  100  parts  of  chloral. 


28  ORGANIC  MEDICINAL  CHEMICALS 

The  resulting  material  is  recrystallised  from  benzol  or 
petroleum  ether. 

Colourless  rhomboidal  crystals  having  a  penetrating 
aromatic  odour  and  an  unpleasant  bitter  taste.  M.p.  50°  ; 
b.p.  94'4°-967°.  Readily  soluble  in  water,  alcohol,  glycerine, 
ether,  and  chloroform.  When  shaken  with  20  parts  by 
weight  of  concentrated  sulphuric  acid  no  colour  should  be 
developed  within  one  hour.  An  aqueous  solution  should  be 
neutral  to  litmus,  and  should  give  no  precipitate  on  addition 
of  silver  nitrate  solution. 

Chloral  hydrate  was  introduced  into  medicine  as  an 
hypnotic  in  1869  by  lyiebreich.  It  quickly  produces  a 
natural  and  placid  sleep,  but  is  not  suitable  for  insomnia 
caused  by  pain.  It  is  employed  in  cases  of  acute  mania  and 
delirium  tremens,  in  asthma  and  whooping  cough,  and  is  of 
great  value  in  midwifery. 

It  is  reduced  in  the  body  to  trichlorethyl  alcohol,  which 
is  eliminated  in  the  form  of  a  compound  with  glycuronic  acid. 

CHLORALOSE  (Chloral  Glucose— Glucochloral) 

C8Hn06Cl3.     309-4 

— Chloralose  is  prepared  (Ber.  22,  1051)  by  heating  together 
for  2  hours  at  100°  equal  quantities  of  distilled  chloral  and 
anhydrous  glucose.  Steam  is  then  blown  through  the  reaction 
mixture,  to  remove  unchanged  chloral,  and,  after  cooling,  the 
mixture  of  chloralose  and  para-chloralose  is  filtered  off.  These 
compounds  are  separated  by  fractional  crystallisation  from 
hot  alcohol,  when  the  para-chloralose,  being  the  less  soluble, 
separates  first ;  or  (Bl.  [3]  9,  17)  by  treatment  with  hot  ether, 
which  removes  para-chloralose,  after  which  the  chloralose 
may  be  finally  purified  by  crystallisation  from  hot  water  or 
alcohol.  Colourless  crystals,  possessing  a  bitter,  disagreeable 
taste;  m.p.  186^87°  (para-chloralose,  m.p.  227°).  Sparingly 
soluble  in  water  (0-65  parts  in  100),  soluble  in  31  parts  of 
91  %  alcohol,  and  in  125  parts  of  ether.  Chloralose  is  em- 
ployed as  a  hypnotic  and  sedative  in  the  insomnia  of  phthisis 
and  mania.  It  is  said  to  act  more  like  morphine  and  to 
possess  a  greater  toxicity  than  chloral  hydrate,  but  patients 
are  said  to  become  rapidly  habituated  to  its  use. 


NARCOTICS  AND  GENERAL  ANESTHETICS    29 

CHLORAL  FORMAMIDE  (Chloralamide) 

CC13CH(OH)NHCHO.    192-4. 

—  Formamide,  45  parts  (for  preparation,  see  J.  Amer.  Chem. 
Soc.  40,  793),  is  added,  with  stirring,  to  cooled,  freshly 
distilled  chloral,  147*4  parts.  Combination  takes  place  with 
evolution  of  heat.  The  mixture  sets,  on  cooling,  to  a  solid 
crystalline  mass  of  chloral  formamide.  (D.  R.  P.  50586  ; 
E.  P.  739i/i886.) 

OH 


>  CC13CH—  NHCHO 

147-4  45  192-4 

The  product  is  purified  by  recrystallising  it  from  dilute 
alcohol.  The  solution  must  not  be  heated  above  48°,  as 
at  higher  temperatures  chloral  formamide  is  reconverted 
into  chloral  and  formamide. 

An  alternative  method  of  preparation  is  by  heating 
together  chloralammonia,  prepared  by  passing  dry  ammonia 
gas  into  a  solution  of  chloral  in  benzene  or  ether,  and  ethyl 
formate. 


164-4  74  !92'4  46 

Colourless  odourless  crystals  ;  m.p.  Ii4°-ii5°.  Soluble 
in  21  parts  of  water  at  20°  and  in  2  parts  of  90  %  alcohol. 
The  aqueous  solution  should  be  neutral  to  litmus,  and  no 
immediate  turbidity  should  be  produced  on  the  addition  of 
silver  nitrate  solution. 

Chloralamide  is  a  hypnotic  possessing  analgesic  as  well 
as  sedative  properties.  Its  action  is  similar  to,  but  slower 
than,  that  of  chloral  hydrate,  than  which  it  is  said  to  be 
less  irritant  to  the  stomach.  It  is  claimed  that  it  has  less 
influence  on  the  heart  than  chloral  hydrate,  but  this  claim 
has  not  been  substantiated. 

BUTYLCHLORAL  HYDRATE  (Trichlorobutyraldehyde  hy- 
drate) CH3-CHC1-CC12-CH(OH)2  (193-4)  is  prepared  by  the 
action  of  chlorine  on  par  aldehyde  in  a  similar  manner  to 
that  by  which  chloral  is  produced  from  alcohol. 


30  ORGANIC  MEDICINAL  CHEMICALS 

The  operation  is  carried  out  in  a  lead  or  porcelain-lined 
vessel  provided  with  stirring  gear,  with  a  jacket  and  internal 
coils  through  which  either  cold  brine,  hot  and  cold  water,  or 
steam  can  be  circulated,  and  with  chlorine  distributing  tubes. 

Chlorination  is  commenced  at  — 5°,  and  the  tempe- 
rature is  not  allowed  to  rise  above  o°  until  complete 
absorption  occurs.  Thereafter  it  is  raised  by  increments 
of  5°  up  to  90°,  whenever  appreciable  quantities  of 
chlorine  are  seen  to  be  escaping  with  the  hydrochloric  acid 
vapour.  The  time  occupied  by  the  whole  operation  depends 
largely,  of  course,  upon  chlorine  distribution  and  upon  the 
efficiency  of  the  stirring  ;  also,  in  the  earlier  stages,  upon 
the  adequacy  of  the  cooling.  It  is  advisable  that  the 
chlorination  should  be  uninterrupted,  as  the  longer  the 
time  taken  the  larger  is  the  quantity  of  the  tarry  condensa- 
tion products  that  are  formed.  When  sufficiently  chlori- 
nated, the  reaction  product  is  subjected  to  steam  distillation. 
Butylchloral  hydrate  passes  over,  and  is  collected  and 
recrystallised  from  water.  Pearly  white  crystals ;  m.p. 
78°.  The  odour  is  pungent  and  somewhat  fruitlike,  and 
should  not  be  acrid.  It  should  not  afford  a  brown  colour 
when  shaken  or  gently  warmed  with  concentrated  sulphuric 
acid,  and  should  be  free  from  hydrochloric  acid  and  chloride 
ions.  It  dissolves  in  44  parts  of  cold,  and  readily  in  hot, 
water.  Readily  soluble  in  alcohol,  glycerine  and  oils. 

Butylchloral  hydrate  is  employed  sometimes  as  a 
hypnotic,  in  this  respect  being  similar  to  but  less  efficient 
than  chloral  hydrate.  It  is  analgesic  and  especially  recom- 
mended for  the  relief  of  facial  neuralgia,  and  in  the  treatment 
of  tic  douloreux. 

CHLORETONE  (Trichloro  tertiary-butyl  alcohol)  (ace- 
tone-chloroform) 

CH3\     /OH 

XC 
CH3/  \CC13 

177-4 

To  a  mixture  of  500  parts  of  dry  acetone  and  1000  parts 
of     chloroform,    cooled    to    below    o°    and    continuously 


NARCOTICS  AND  GENERAL  ANAESTHETICS    31 

stirred,  are  added  gradually,  over  a  period  of  2|  days, 
325  parts  of  finely  powdered  caustic  potash.  After  being 
allowed  to  stand  at  room  temperature  for  a  further  ij  days 
with  intermittent  stirring  the  mass  is  filtered  and  the  residue 
washed  with  acetone.  The  combined  filtrate  and  washings 
are  distilled ;  unchanged  chloroform  and  acetone  are 
recovered,  and  the  fraction  passing  over  between  165°  and 
172°  is  collected  separately  and  shaken  with  water.  Crys- 
tallisation sets  in,  and  when  this  is  complete  the  solid  is  filtered 
ofl  and  recrystallised  from  a  mixture  of  alcohol  and  water 
(/.  pr.  Chem.  37,  362).  It  is  extremely  volatile  even  at 
ordinary  temperatures,  and  requires  to  be  dried  with  great 
care  to  avoid  loss. 

White  glistening  crystals  having  a  camphoraceous  odour 
and  taste  ;  m.p.,  when  anhydrous,  g6°-gy°.  Soluble  in 
125  parts  of  water  ;  in  f  part  of  90  %  alcohol. 

Chloretone  has  an  action  similar  to  that  of  chloral  hydrate 
on  the  central  nervous  system,  and  is  used  in  the  treatment 
of  insomnia,  vomiting,  and  spasmodic  conditions,  being  less 
liable  to  irritate  the  stomach.  It  is  employed  as  an  intro- 
ductory to  general  anaesthesia,  excitement  and  nausea 
being  thereby  lessened.  It  is  a  mild  local  anaesthetic  and 
possesses  antiseptic  properties.  Both  chloretone  and  its 
condensation  product  with  chloral 


m.p.  65' 
are  said  to  be  efficient  preventives  of  sea-sickness. 

THE   SUIyPHONE   HYPNOTICS. 
Sulphones  of  the  type  : — 

RlS°2\c/R3 
R2S02/  \R4 

possess  remarkable  narcotic  properties  when  the  radicles 
are  alkyl  groups  of  which  at  least  two  are  ethyl.  The 
physiological  activity  of  an  equal  concentration  of  these 


32  ORGANIC  MEDICINAL  CHEMICALS 

compounds  increases  according  as  two,  three,  or  four  of 
these  radicles  are  ethyl  groups.  Sulphonal  is  a  substance 
of  the  above  formula,  in  which  Rx  and  R2  are  ethyl  groups, 
R3  and  R4  being  methyl.  In  Trional  there  are  three,  and 
in  Tetronal  four,  ethyl  radicles. 

According  to  Meyer,  the  physiological  effect  of  the  three 
substances  may  be  expressed  by  the  ratio  : — 

Sulphonal 6 

Trional 13 

Tetronal 18 

SULPHONAL  (Diethyl-sulphone-dimethyl-methane) 
C2H5S02\x  /CHg 

C2H5S02/  \CH3 
0-228 

Sulphonal  is  prepared  by  condensing  ethyl  mercaptan 
with  acetone, 

2C2H6SH+CO(CH3)2  ->  (C2H6S)2C(CH3)2+H20 
124  58  164 

and  the  resulting  acetone  ethyl  mercaptol  is  oxidised  to 
the  sulphone,  sulphonal. 

Preparation  of  Ethyl  Mercaptan  C2H5SH.— Ethyl  mer- 
captan is  made  by  the  interaction  of  potassium,  or  sodium, 
hydrogen  sulphide,  KHS  or  NaHS,  with  sodium  ethyl 
sulphate  or  with  ethyl  chloride  (Rengault,  Ann.  34,  25). 

Two  parts  by  volume  of  99  %  alcohol  are  added  to  a 
mixture  of  i  part  by  volume  of  sulphuric  acid  (sp.gr.  1-84) 
and  i  part  of  20  %  fuming  sulphuric  acid,  the  temperature 
being  kept  below  70°.  The  mixture  is  allowed  to  cool 
overnight,  diluted  with  crushed  ice,  and  poured  on  to  a 
mixture  of  ice  and  a  solution  containing  8  parts  by  weight 
of  sodium  carbonate  crystals,  with  stirring.  More  sodium 
carbonate  is  added  if  necessary,  and  the  neutral  solution  is 
concentrated  until  a  crust  of  salt  forms  on  the  surface.  On 
cooling,  most  of  the  sodium  sulphate  separates  out,  and  is 
filtered  off.  The  filtrate,  measuring  about  3  volumes,  is 
mixed  with  a  solution  of  potassium  sulphide,  prepared  by 


NARCOTICS  AND  GENERAL  ANESTHETICS    33 

saturating  with  H2S  a  solution  of  1*6  parts  by  weight  of 
KOH  in  3  parts  by  volume  of  water.  The  mixture  is 
gradually  heated,  and  the  ethyl  mercaptan  distilled  over. 
It  is  freed  from  ethyl  sulphide  by  treatment  with  con- 
centrated NaOH  solution,  in  which  ethyl  mercaptan  dis- 
solves. Any  undissolved  oil  is  separated,  after  which  the 
mercaptan  is  reprecipitated  by  addition  of  acid. 

Mercaptan  may  also  be  prepared  from  ethyl  chloride  by 
the  following  method.  A  solution  of  potassium  (or  sodium) 
hydrogen  sulphide  is  treated  with  ethyl  chloride  in  a  jacketed 
autoclave,  fitted  with  a  stirrer  and  connected  to  a  condenser. 
Slightly  more  than  one  molecule  of  ethyl  chloride  is  required, 
some  alcohol  also  being  added  to  facilitate  reaction.  The 
mixture  is  gently  warmed,  with  continuous  stirring,  to  50°- 
60°,  and  maintained  at  this  temperature  until  the  titration 
of  test  portions  with  acid,  using  methyl  orange  as  indicator, 
shows  the  reaction  to  be  completed.  The  ethyl  mercaptan, 
which  is  mixed  with  alcohol  and  some  diethyl  sulphide,  is 
distilled  over,  converted  into  its  sodium  salt,  after  which 
the  alcohol  and  diethyl  sulphide  are  removed  by  a  second 
distillation,  and  reprecipitated  by  the  addition  of  acid,  as 
mentioned  above. 

Ethyl  mercaptan  boils  at  36°  ;  it  is  nearly  insoluble  in 
water. 

Preparation  of  Acetone  Ethyl  Mercaptol 


(Ber.  19,  2803).  One  part  of  acetone  is  mixed  with  2|  parts 
of  ethyl  mercaptan  (20  %  excess)  and  the  mixture  treated 
with  dry  hydrogen  chloride,  the  temperature  being  kept, 
by  cooling,  below  25°.  The  condensation  may  be  facili- 
tated by  the  presence  of  anhydrous  calcium  chloride,  which 
serves  to  remove  the  water  formed  by  the  reaction.  When 
saturated  with  HC1  the  mixture  is  left  to  stand  overnight  ; 
then  washed  with  water.  The  mercaptol  layer  is  dried 
over  CaCl2  and  fractionally  distilled.  Unchanged  ethyl 
mercaptan  passes  over  first,  the  mercaptol  distilling  at 


34  ORGANIC  MEDICINAL  CHEMICALS 

Oxidation  of  Acetone  Ethyl  Mercaptol  to  Sulphonal  (Ber. 
19,  280). — To  acetone  ethyl  mercaptol,  164  parts,  are 
added,  with  violent  agitation,  5000  parts  of  a  5  %  solution 
of  potassium  permanganate.  The  mixture  warms  itself  as 
oxidation  proceeds.  Solid  potassium  permanganate  is  added 
from  time  to  time,  to  maintain  the  concentration,  until,  in 
all,  about  420  parts  have  been  used.  Stirring  is  continued 
until  the  permanganate  has  been  practically  all  consumed, 
after  which  the  temperature  is  raised  to  boiling,  the  solution 
decolorised,  if  necessary,  by  addition  of  sodium  bisulphide, 
and  filtered.  From  the  filtrate  sulphonal  separates  on 
cooling,  and  is  filtered  off  and  purified  by  recrystallisation 
from  aqueous  alcohol. 

By  another  method  sulphonal  is  made  from  ethylidene 
diethyl  sulphone,  acetaldehyde  taking  the  place  of  acetone. 

Acetaldehyde  (b.p.  21°)  44  parts,  (i  molecule),  is  mixed 
with  ethyl  mercaptan  124  parts,  (2j  mols.),  when  interaction 
occurs  with  the  evolution  of  heat.  Anhydrous  zinc  chloride 
is  added,  with  good  cooling.  After  standing  for  some  time 
the  mercaptol  is  separated  from  the  layer  of  aqueous  zinc 
chloride,  and  is  washed  with  water,  dried,  and  distilled ; 
b.p.  i85°-i87°.  The  mercaptol  is  oxidised  with  potassium 
permanganate  solution  to  the  corresponding  sulphone 
CH3CH(SO2C2H5)2  in  the  same  way  as  before,  and  this  is 
converted  into  sulphonal  by  boiling  an  alcoholic  solution  of 
the  sodium  salt  with  methyl  iodide. 

(C2H5S02)2CCH3Na+CH3I  ->  (C2H5SO2)2C(CH3)2+NaI. 
236  142  228  150 

Sulphonal  forms  colourless,  odourless,  almost  tasteless 
prismatic  crystals.  It  dissolves  in  400  parts  of  cold,  and  in 
15  parts  of  boiling,  water.  It  is  readily  soluble  in  alcohol, 
i  in  80,  and  in  chloroform.  M.p.  125-5°.  The  aqueous 
solution  should  be  neutral  in  reaction,  and  should  not  give 
the  reactions  of  chlorides  or  sulphates.  The  solution  in 
boiling  water  should  be  free  from  odour,  showing  absence 
of  mercaptan  and  mercaptol.  The  aqueous  solution  (10  c.c.) 
should  not  be  immediately  decolorised  after  addition  of  a 


NARCOTICS  AND  GENERAL  ANESTHETICS    35 

drop  of  potassium  permanganate.  Its  physiological  pro- 
perties are  compared  to  those  of  other  sulphones,  p.  36. 

TRIONAL    (Methyl     sulphonal.      Diethyl-stilphone-ethyl 
methyl  methane) 

C2H5S02\     /CH3 

1^ 

C2H6S02/  \C2H5 

242 

Methyl  ethyl  ketone  and  ethyl  mercaptan  are  condensed  to 
the  mercaptol,  which  is  oxidised  in  the  same  way  as  has 
been  described  under  "Sulphonal"  (D.  R.  P.  49073).  The 
conditions  to  be  observed  are  materially  the  same.  Ethyl 
methyl-ketone-ethyl  mercaptol ;  b.p.  I98°-203°. 
Alternatively,  the  ethylidene  diethyl  sulphone 

CH3CH(S02C2H5)2, 

described  under  "  Sulphonal,"  may  be  ethylated,  by  treat- 
ment with  sodium  ethylate  and  ethyl  iodide  in  absolute 
alcohol,  when  trional  is  afforded.  The  ethylation  is  stated 
not  to  proceed  well,  much  substance  remaining  unchanged. 
Trional  is  a  white  crystalline  powder,  which  melts  at  76'5°. 
It  dissolves  in  400  parts  of  cold  water,  giving  a  neutral 
solution  ;  it  is  readily  soluble  in  alcohol.  Trional  should 
comply  with  the  same  tests  as  sulphonal  for  absence  of 
impurities. 

TETRONAL    (Ethyl    sulphonal— Diethyl-sulphone-diethyl 
methane) 

C2H5S02\      /C2H5 
CT 

C2H5S02/    \C2H5 

256 

Ethyl  mercaptan,  7  parts,  is  mixed  with  5  parts  of  diethyl 
ketone ;  the  mixture  is  cooled  with  ice  and  saturated  with 
dry  HC1.  Condensation  is  completed  in  a  few  hours  and 
the  mercaptal  is  then  washed  with  water  and  distilled  ; 
b.p.  225°-230°.  It  is  oxidised  to  the  sulphone,  tetronal, 
in  the  manner  described  under  "  Sulphonal."  (D.  R.  P.  49366 ; 
E.  P.  12563/1888.) 

Tetronal  crystallises  in  silvery  leaflets  ;   m.p.  85°  C.     It 


36        ORGANIC  MEDICINAL  CHEMICALS 

dissolves  in  500  parts  of  cold  water,  and  in  12  parts  of 
90  %  alcohol.  It  should  comply  with  the  same  exclusive 
tests  as  sulphonal. 

The  three  sulphone  methanes  described  above,  when 
administered  in  therapeutic  doses,  produce  sleep  without 
noticeable  effect  on  the  circulation  and  respiration.  Sul- 
phonal is  the  most  generally  used  ;  trional  is  next  in  import- 
ance ;  tetronal  is  but  little  used.  The  action  of  sulphonal 
is  more  slowly  established  than  that  of  trional,  probably 
on  account  of  its  lesser  solubility.  The  low  solubility  of  the 
sulphones  renders  them  somewhat  uncertain  in  their  action. 

Hypnotic  action  is  not  exhibited  by  disulphones  which 
do  not  contain  ethyl  groups.  Thus  dimethyl-sulphonedi- 
methyl-methane  (CH3)2C(SO2CH3)2  is  without  hypnotic 
action. 

Dimethyl-sulphone-ethyl-  methyl  methane 

/C(SO2CH3)2 


has  a  slight  hypnotic  action  ;  whilst  sulphonal 
(CH3)2C(S02C2H6)2 

and  the  isomeric  dimethyl  -  sulphone  -  diethyl  -  methane 
(C^g  )2C(SO2CH  3)  2  possess  a  considerable  and  equal  hypnotic 
effect. 

DERIVATIVES  OF  UREA. 

The  constitution  of  a  large  number  of  compounds  of 
significance  in  biochemistry  includes  the  carbamic  acid 
grouping.  The  Narcotics,  which  are  esters  and  derivatives 
of  carbamic  acid,  comprise  a  very  important  class.  The 
physiological  activity  of  these  urethanes  is  traceable  chiefly 
to  their  physical  properties  and  to  the  presence  of  ethyl 
groups,  and  is  not  commonly  attributed  to  the  carbamic 
residue.  Ethyl  urethane,  methylpropylcarbinylurethane, 
tertiary  amyl  urea,  diethyl  malonyl  urea,  etc.,  constitute  a 
series  of  hypnotics,  the  commercially  important  members  of 
which  are  here  described. 

The  action  of  adalin  and  veronal  seems  to  be  confined  to 


NARCOTICS  AND  GENERAL  ANESTHETICS    37 

the   central  nervous   system,    and   they   are   consequently 
preferred  to  all  other  hypnotics  when  sleep  alone  is  sought. 


URETHANE    (Ethyl   carbamate)    CCKQ^  |j       89.—  Ure- 

thane  can  be  prepared  from  ethyl  chloroformate  by  the 
action  of  ammonia,  or  by  the  interaction  of  urea  nitrate, 
or  urea  chloride,  or  isocyanic  acid,  with  alcohol. 

i.  From  Ethyl  chloroformate.  —  Ethyl  chloroformate  is 
made  — 

(a)  (D.  R.  P.  117624)  By  the  interaction  of  molecular  pro- 
portions of  phosgene  and  antipyrine  in  benzene  solution.  A 
double  compound  is  formed,  which,  treated  with  absolute 
alcohol,  is  dissociated  into  antipyrine  hydrochloride  and 
ethyl  chloroformate. 


(b)  (D.  R.  P.  251805)  To  250  parts  of  a  20  %  solution  of 
phosgene  in  ether  are  added  gradually,   with  cooling,   23 
parts  of  absolute  alcohol  diluted  with  some  ether,  followed 
by  54  parts  of  technical  monomethyl  aniline  in  an  equal 
volume    of   ether.     After   the    reaction    is    completed   the 
solution  is  shaken  out  with  dilute  acid  to  remove  the  methyl 
aniline,  dried,  and  fractionally  distilled. 

(c)  Phosgene  is  passed  slowly  into  ethyl  alcohol  cooled 
by  a  freezing  mixture,  the  reaction  mixture  is  poured  into 
a  little  water,  dried,  and  distilled. 

Ethyl  chloroformate  distils  at  93°. 

To  obtain  ure  thane  from  ethyl  chloroformate,  the  latter 
is  added,  with  vigorous  stirring,  to  an  excess  of  O'88o 
ammonia,  cooled  to  io°-i5°  by  external  cooling.  (Ann.  IO, 
284.) 

CO  2NH  **  CO 


OC2H6  3  2H6 

108*4          o*34  0-89          53-4 

It  may  also  be  prepared  by  passing  ammonia  gas  into  an 
ethereal  solution  of  ethyl  chloroformate.  The  reaction 
mixture  is  evaporated  to  remove  excess  of  ammonia,  and 
the  urethane  extracted  with  ether,  and,  after  removal  of 


38  ORGANIC  MEDICINAL   CHEMICALS 

the   solvent,   distilled  in   vacuo.     B.p.    172°  at  760  mm.  ; 
m.p.  48°. 

(2)  From  Potassium  Isocyanate  (Folim,  Am.  Chem.  J.  19, 
341). — Five  parts  of  potassium  isocyanate  are  dissolved  in 
sufficient  warm  50%  alcohol  to  give  a  clear  solution.     This 
is  added  slowly   to   a  concentrated   alcoholic  solution   of 
hydrochloric  acid,  containing  excess  of  acid.     The  mixture 
is  allowed  to  stand  for  24  hours,  neutralised  with  barium 
carbonate,  filtered,  and  freed  from  alcohol  by  distillation 
under  reduced  pressure.     From  the  residual  liquid  ure thane 
is  extracted  with  ether.     Yield,  60  %  of  the  theoretical. 

CO=NH+C2H5OH  ->  C 

(3)  From  Carbamic  chloride  (Ann.  244,  40). — Carbamic 
chloride  (prepared  by  the  action  of  phosgene  on  ammonium 
chloride)  is  added  slowly  to  an  excess  of  absolute  alcohol. 

The  reaction  mixture  is  treated  with  water,  and  the 
urethane  extracted  with  ether.  A  quantitative  yield  is  said 
to  be  afforded  by  this  method. 

Urethane  forms  colourless,  odourless  crystals,  m.p.  48°, 
possessing  a  peculiar  "  cool "  taste.  It  dissolves  in  2  parts  of 
water,  and  in  i  part  of  alcohol  90  %.  A  10  %  aqueous 
solution  should  give  no  reaction  for  chloride  or  nitrate. 

Urethane  is  employed  as  a  mild  narcotic.  Compared 
with  chloral  hydrate  it  has  little  action  on  the  blood  pressure 
and  does  not  affect  the  heart.  It  is  especially  suitable  for 
children.  It  is  oxidised  in  the  system  to  carbon  dioxide  and 
urea. 

HEDONAL  (Methylpropylcarbinyl  urethane) 


CC3^7>CHOCONH2,     131. 


Methylpropylcarbinyl  urethane  (hedonal)  has  an  hypnotic 
action  twice  as  powerful  as  that  of  urethane.  It  is  said 
to  have  no  action  on  the  circulation  or  respiration,  and  to 
be  useful  in  insomnia. 

According  to  D.  R.  P.  114396,  methylpropylcarbinol, 
20  parts,  is  mixed  with  28  parts  of  urea  nitrate,  and  the 


NARCOTICS  AND  GENERAL  ANESTHETICS    39 

mixture  heated  in  a  closed  vessel  under  pressure  for  5-6 
hours  at  I25°-I30°.  When  cold  a  small  quantity  of  water 
is  added  to  the  mass,  and  the  oily  liquid  which  separates  is 
isolated  from  the  aqueous  solution.  On  standing  it  solidifies, 
and  is  purified  by  recrystallisation  from  light  petroleum. 
An  alternative  method  of  preparation  is  by  the  action 
of  ammonia  on  methylpropylcarbinyl  chlorocarbonate 

C°H3/CHOCOC1  (D-  R'  P'  I2o863)-  The  chlorocarbonic 
ester  may  be  obtained  (D.  R.  PP.  117624,  118536,  118537) 
by  combining  phosgene  with  a  molecular  proportion  of  a 
tertiary  base,  such  as  antipyrine  or  dime  thy  laniline.  The 
resulting  double  compound  is  treated,  in  benzene  or  ether 
solution,  with  a  molecular  proportion  of  the  alcohol,  in  this 
case  methylpropylcarbinol,  when  the  hydrochloride  of  the 
base  and  the  chlorocarbonic  ester  are  produced.  The  former 
is  washed  out  with  dilute  hydrochloric  acid,  the  solvent 
removed,  and  the  ester  distilled. 

R3N+COC12  ->  R3  ;  N< 

co-c 

->  R 

Five  parts  of  methylpropylcarbinyl  chlorocarbonate  ester 
dissolved  in  10  parts  of  benzene  are  treated,  whilst  being 
cooled  and  stirred,  with  20  %  aqueous  ammonia  (2  mols.) 
and  agitated  until  the  odour  of  the  ester  has  disappeared. 
After  standing  for  one  hour  the  benzene  layer  is  isolated  and 
the  benzene  distilled  off,  when  the  urethane  is  obtained. 
(Cf.  also  D.  R.  PP.  120864  and  120865.) 


A  white  crystalline  powder,  having  a  faint  aromatic 
odour  and  taste.  M.p.  74°  ;  b.p.  215°. 

Slightly  soluble  in  cold  water,  readily  soluble  in  alcohol, 
ether,  chloroform,  and  other  organic  solvents. 

Hedonal  is  used  as  an  hypnotic  in  cases  of  insomnia  due 


40  ORGANIC  MEDICINAL   CHEMICALS 

to  mental  overwork,  or  nervous  excitement  due  to  neuras- 
thenia or  hysteria.  It  is  stated  to  have  a  greater  hypnotic 
effect  than  ethyl  carbamate,  and  its  use  to  be  unattended 
by  deleterious  after-effects. 

ADALIN  (Bromodie  thy  lace  tyl  urea) 

(C2H5)2CBrCONH-CONH2.     237. 

In  considering  the  manufacture  of  the  important  narcotics 
of  this  group  the  preparation  of  the  intermediate  substance, 
diethylmalonic  ester,  and  from  it  of  diethylacetic  acid,  will 
first  be  described.  The  group  includes,  besides  adalin, 
veronal  or  diethylbarbituric  acid,  proponal  or  dipropyl- 
barbituric  acid,  luminal  or  phenylethylbarbituric  acid. 

/POOP  TT 

Malonic    Ester    CH2<^£QQ£2£[5     I^°   (see  Amer.  Journ. 

of  Science,  26,  269  (1908)). — Monochloroacetic  acid,  200 
parts,  is  mixed  with  water,  50  parts,  and  neutralised  by 
the  addition  of  300  parts  of  crystallised  sodium  car- 
bonate. The  solution  is  heated  to  80°  and  poured,  with 
rapid  stirring,  into  a  solution  of  125  parts  of  sodium 
cyanide  in  250  parts  of  water,  heated  to  9O°-95°,  and, 
after  the  reaction  has  subsided,  the  mixture  is  boiled  for 
several  minutes.  It  is  then  cooled  and  neutralised  with 
sulphuric  acid,  using  logwood  paper  as  an  indicator.  The 
separated  salt  is  filtered  off,  and  the  filtrate  evaporated 
to  dry  ness  in  vacuo  at  60°.  The  salt  is  washed  with  200 
parts  of  94  %  alcohol,  filtered,  the  filtrate  added  to  the 
residue  obtained  from  the  evaporation,  warmed  and  again 
filtered.  The  solid  is  washed  with  a  further  similar  quantity 
of  alcohol,  and  the  two  alcoholic  filtrates  are  combined  and 
evaporated  under  diminished  pressure.  The  dry  residue 
is  mixed  with  600  parts  of  absolute  alcohol,  10  parts  by 
weight  of  sulphuric  acid  (sp.gr.  1*84)  added,  the  mixture  cooled 
to  below  o°,  and  saturated  with  dry  hydrochloric  acid  gas. 
After  standing  for  2  hours  the  solution  is  boiled  for  2  hours, 
then  cooled  and  filtered.  The  solid  is  washed  with  100 
parts  of  absolute  alcohol,  which  is  then  mixed  with  the 
previous  filtrate.  The  mixture  is  boiled,  and  the  vapour  of 
700  parts  of  absolute  alcohol  passed  through  it,  in  3-4  hours. 


NARCOTICS  AND  GENERAL  ANESTHETICS    41 

Part  of  the  alcohol  is  then  distilled  off,  and  the  residue,  after 
cooling,  poured  on  to  ice.  The  ethyl  malonate  is  extracted 
with  ether,  washed  with  an  alkaline  carbonate,  dried  with 
calcium  chloride,  and  distilled  in  vacuo,  after  removal  of 
the  solvent.  A  yield  of  85-88  %  is  claimed  by  this  method. 

B.p.  198°. 

/POOO  TT 
Diethylmalonic  Ester  (^HsUC^QQ^2-^5    216. — Sodium, 

23  parts,  is  dissolved  in  absolute  alcohol,  treated  with 
ethyl  malonate,  i  molecule,  160  parts,  and  slightly  more 
than  i  molecule  of  dry  ethyl  iodide  or  ethyl  bromide.  The 
mixture  is  refluxed  until  neutral,  the  alcohol  is  distilled  off, 
the  cooled  residue  treated  with  water,  and  the  monoethyl 
malonic  ester  extracted  and  rectified.  The  second  ethylation 
is  brought  about  by  a  repetition  of  this  process  under 
identical  conditions,  whereby  diethyl  malonic  ester  is 
produced.  B.p.  ig5°-205°. 

Diethylacetic  Acid  (C2H5)2CHCOOH.  116.— One  mole- 
cule of  diethylmalonic  ester  is  heated  with  an  aqueous 
solution  of  2  molecules  of  caustic  soda  until  neutral  to 
phenolphthalein,  or  until  the  alkalinity  to  this  indicator  no 
longer  decreases.  The  alcohol  is  distilled  off,  the  residue 
cooled  and  treated,  whilst  stirring,  with  an  amount  of 
concentrated  hydrochloric  acid  equivalent  to  the  caustic 
soda  employed.  An  oil  separates  which  presently  solidifies, 
and  consists  of  diethylmalonic  acid.  This  is  filtered  off 
and  recrystallised  from  benzene,  after  which  it  should 
melt  sharply  at  121°. 

It  is  converted  into  diethylacetic  acid  by  heating  to  180° 
in  vacuo  in  an  oil-jacketed  still  provided  with  stirring  gear 
and  a  condenser.  After  the  evolution  of  CO2  is  complete 
the  temperature  is  raised  until  the  diethylacetic  acid 
distils  over. 

Bromodiethylacetyl  Bromide. — Diethylacetic  acid  is  treated 
with  phosphorus  and  bromine  according  to  Volhard's  well- 
known  method  (Ann.  242,  141). 

3(C2H5)2CHCOOH+P+5Br->3(C2H6)2CHCOBr+HP02+2HBr 
3(C2H6)2CHCOBr+6Br  ->  3(C2H6)2CBrCOBr+3HBr 


42  ORGANIC  MEDICINAL  CHEMICALS 

The  components  are  reacted  at  as  low  a  temperature  as 
possible,  5o°-6o°,  and  the  resulting  acid  bromide  is  isolated 
from  the  hypophosphorous  acid  and  freed  from  hydrobromic 
acid  by  aspirating  through  it  a  current  of  dried  air  or 
carbon  dioxide.  Lastly  it  is  distilled  in  vacuo. 

Bromodiethylacetyl  urea  (D.  R.  P.  225710). — Pure  bromo- 
diethyl  acetyl  bromide,  258  parts,  is  mixed  with  dry 
powdered  urea,  122  parts,  and  the  mixture  allowed  to  re- 
main at  atmospheric  temperature  for  12  hours,  with  inter- 
mittent stirring,  after  which  it  is  heated  on  a  water-bath 
at  6o°-7o°  for  3  hours.  When  cold,  the  reaction  product 
is  powdered,  treated  with  water,  and  sodium  bicarbonate 
added  until  alkaline.  The  undissolved  material  consists 
of  bromodiethylacetyl  urea,  and  is  filtered  off,  washed,  and 
dried,  after  which  it  is  recrystallised.  In  view  of  the  fact 
that  on  heating  with  water  it  loses  HBr,  giving  diethyl 

CO-NH 
hydantoin    (C2H5)2C</  |      (m.p.  181°)  (Ber.  d.  deutsch. 

"NH-CO 

pharm.  Ges.  21,  96  (1912)),  crystallisation  is  best  carried 
out  in  an  anhydrous  solvent,  such  as  benzene,  or  ligroin, 
but  it  may  be  crystallised  from  alcohol. 

Many  alternative  methods  of  preparation  have  been 
protected,  of  which  the  following  is  a  summary  : — 

From  bromodiethylcyanamide  (C2H5)2CBrC(>NH-CN  by 
hydrolysis  with  concentrated  sulphuric  acid  (D.  R.  P. 
225710). 

By  the  bromination  of  diethylacetyl  urea  (D.  R.  P.  225710) . 

Oxidation  of  bromodiethyl  thiourea  with  KMnO4  (D.  R.  P. 
225710). 

From  bromodiethylacetyl  phenyl  carbamate  (D.  R.  P. 
225710). 

By  heating  bromodiethylacetyl  isourea  methyl  ether  with 
HC1  (D.  R.  PP.  240353  and  243223). 

By  the  action  of  HCNO  on  bromodiethylacetamide 
(D.  R.  P.  249906). 

By  treating  bromodiethylacetyl  carbamide  chloride  with 
ammonia  (D.  R.  P.  249906). 


NARCOTICS  AND  GENERAL  ANESTHETICS    43 

By  treating  bromodiethyl  acetyl  cyanate  with  ammonia 
(D.  R.  P.  271682). 

By  interaction  of  bromodiethyl  acetamide  and  carbamic 
chloride  (D.  R.  P.  262148). 

Adalin  is  a  colourless,  crystalline  powder,  m.p.  115°- 
116°,  containing  35-8  %  Br.  It  is  slightly  soluble  in  cold 
water,  and  in  cold  benzol  or  ligroin,  and  readily  soluble  in 
alcohol  or  acetone. 

Adalin  is  a  mild  and  promptly  acting  sedative,  the  use 
of  which  is  associated  with  no  unpleasant  sequelae.  It  is 
employed  as  a  sedative  in  cases  of  neurasthenia,  hysteria, 
and  insomnia,  and  for  mental  disorders. 

VERONAL  (Barbitone  —  diethylbarbituric  acid  —  die  thy  1 

malonylurea)(C2H5)2C<cO-NH/Ca  C8Hi2N2O3.  184.- 
This  useful  hypnotic  has  attained  great  commercial  im- 
portance. A  very  large  number  of  patents  cover  its  prepara- 
tion. The  two  methods  which  are  of  greatest  technical 
importance  are  described  in  some  detail ;  the  others  are 
merely  enumerated. 

(i)  By  the  Condensation  of  Diethylmalonic  ester  and  Urea 
(D.  R.  P.  146496). — For  the  preparation  of  diethylmalonic 
ester,  see  "Adalin,"  p.  40.  Sodium,  32  parts  (3  mols.),  is 
dissolved  in  absolute  alcohol  (600  parts),  and  to  the  cooled 
solution  40  parts  of  dry  urea  and  100  parts  (i  mol.)  of 
diethylmalonic  ester  are  added.  The  mixture  is  heated 
under  pressure  in  an  autoclave  at  ioo°-no°  for  4-5  hours. 
After  cooling,  the  sodium  salt  of  diethylbarbituric  acid  is 
filtered  off  and  the  filtrate  reheated,  when  a  further  crop 
may  be  obtained. 

The  sodjum-veronal  is  dissolved  in  water  and  the 
solution  acidified  with  hydrochloric  acid.  The  product 
is  filtered  off  and  crystallised  from  water,  a  decolourising 
agent,  such  as  vegetable  charcoal,  being  employed  if 
necessary. 

By  a  modification  of  the  above  process,  which  is  said 
(/.  Amer.  Chem.  Soc.  40,  725)  to  afford  higher  yields, 


44        ORGANIC  MEDICINAL   CHEMICALS 

anhydrous  methyl  alcohol  is  employed  in  place  of  ethyl 
alcohol. 

5  ,  NH 

6  -i-NH 

216  60 


184 

(2)  From  Diethyl-cyanoacetic  Ester  (D.  R.  PP.  156384, 
156385).  —  46  parts  of  sodium  are  dissolved  in  800  parts  of 
absolute  alcohol,  and,  after  cooling,  70  parts  of  powdered 
urea  and  169  parts  of  diethyl-cyanoacetic  ester  added,  and 
the  mixture  refluxed  for  3  hours.  The  alcohol  is  then 
distilled  off,  the  residue  dissolved  in  water,  extracted  with 
ether,  neutralised  with  concentrated  hydrochloric  acid,  and 
the  precipitated  iminodiethyl  malonyl  urea  purified  by 
recrystallisation  from  water.  M.p.  195°. 

/CN 


169  60 

NH 


100  parts  of  iminodiethyl  malonyl  urea  are  dissolved  in 
500  volumes  of  3*3  N-hydrochloric  acid,  and  the  solution 
is  boiled  for  a  short  time.  Diethyl  barbituric  acid  crystallises 
out  on  cooling,  and  is  filtered  off  and  recrystallised  from 
water.  The  acid  filtrate  may  be  used,  after  raising  the 
concentration  again  to  3*3  N,  for  the  hydrolysis  of  a  further 
quantity  of  the  imino  acid. 

NH 


183  184 

(3)  From  Diethylmalonyl  Chloride  and  Urea  (D.  R.  PP. 


NARCOTICS  AND  GENERAL  ANESTHETICS    45 

146949,  182764).  —  Diethyl  malonic  acid  (i  mol.)  is  warmed 
gently  with  phosphorus  pentachloride  (2\  mol.),  the 
diethylmalonyl  chloride  is  separated  from  phosphorus 
oxy  chloride,  and  purified  by  distillation.  B.p.  197°.  (Ber. 

35,  854). 

Diethylmalonyl  chloride,  3  parts,  is  mixed  with  1-9 
parts  of  finely  powdered  dried  urea  and  heated  for  20  hours 
at  9O°-ioo°.  Hydrochloric  acid  is  evolved,  and  finally 
there  remains  a  solid  mass  which,  on  crystallisation  from 
hot  water,  affords  pure  veronal  (D.  R.  P.  146949). 

NH2\  /CO-NH\ 


196-8  60  184 

Veronal  forms  colourless,  odourless  crystals,  possessing 
a  faintly  bitter  taste  ;  m.p.  191°.  It  is  sparingly  soluble 
in  cold  water  (i  in  160),  more  readily  in  hot  water,  and 
fairly  soluble  in  aqueous  solutions  of  alkalis  ;  it  dissolves 
(i  in  8J)  in  90%  alcohol. 

Veronal-sodium,  known  as  Medinal,  is  readily  soluble  in 
water,  and  is  consequently  a  useful  form  for  administration, 
especially  per  rectum.  Veronal  is  one  of  the  most  widely 
used  synthetic  hypnotics,  on  account  of  its  relatively  low 
toxicity  and  comparative  freedom  from  harmful  by-effects. 
It  produces  quiet,  deep  sleep  within  an  hour  of  administra- 
tion. I/arge  doses  cause  death.  It  is  of  little  value  where 
there  is  pain  and  in  such  cases  it  is  of  advantage  to  administer 
aspirin  at  the  same  time.  When  taken  internally,  62  % 
is  said  to  be  eliminated  unchanged,  and  subsequently  to  be 
found  in  the  urine. 

Veronal  and  its  homologues  can  also  be  made  from  the 
following  substances  : 

C-Monoalkylbarbituric  acid  by  alkylation  (D.  R.  P. 
144432). 

Dialkylmalonic  esters,  urea,  acyl  urea,  or  alkyl  urea, 
and  alcoholates,  alkali  metals,  alkaliamides,  or  disodium- 
cyanamide  (D.  R.  PP.  147278,  147279,  147280,  178935). 

2:4-diimino-5-dialkyl-6-oxypyrimidine  with  acids  (D.  R. 
PP.  158592,  162657,  168405  (158581),  180669). 


46  ORGANIC  MEDICINAL  CHEMICALS 

Dialkylated  2-thio-4'6-dioxypyrimidines  (D.  R.  PP. 
162219,  165649,  172404). 

Dialkylthiobarbituric  acids  (D.  R.  P.  170907). 

5-dialkyl-2-thio-4-imino-6-oxypyrimidines  (A.  P.  751724  ; 
D.  R.  P.  173241). 

Dialkylmalonyl  chloride  and  biuret  (D.  R.  PP.  162220  ; 

183857). 

Dialkylmalonyl  halides  and  allophanic  esters  (D.  R.  P. 

177694). 

Dialkylmalonamic  acid  ester  (D.  R.  PP.  162280,  182045, 
163200,  171294). 

Dialkylmalonyl  diurethanes  (D.  R.  PP.  171992,  172886, 
172885,  179946,  183628). 

Dialkylmalonyl  diamides  and  carbonic  esters  (D.  R.  PP. 
163136,  169406,  168407). 

Dialkylmalonyl  diamides  and  phosgene  (D.  R.  P. 
167332). 

Cyanodialkylacetyl  urea  (D.  R.  P.  165225). 

5-dialkyl-4'6-diamino-2-oxy-(D.  R.  P.  166448),  or  4-6- 
triamino-pyrimidines  (D.  R.  PP.  165692,  165693). 

Pyrimidine  derivatives  from  dialkylcyaonacetic  ester, 
malonic  esters,  etc.,  with  dicyandiamides  or  guanylurea 
(D.  R.  PP.  158591,  170586,  165223,  180119,  187990). 

CC-dialkyl  2-arylimino  and  2-arylhydrazine  barbituric 
acid  (D.  R.  PP.  166266,  172979). 

CC-dialkyl  mono-  di-,  tri-iminobarbituric  acids  (D.  R.  P. 

175592). 

Guanyldiethyl  barbituric  acid  (D.  R.  P.  17147). 

Dialkylmalonuric  acid  amides  (D.  R.  P.  174178). 

5  -  Diethyl  -  2*4  -  diamino  -  6  -  oxypyrimidine  (D.  R.  P. 
180669). 

Diethylmalonyl  guanidine  (D.  R.  PP.  189076,  201244). 

Diethylmalonic    acid    tetraalkyl    diureides    (D.    R.    P. 

193446). 

Dialkylmalonyl  halogenides  and  isourea  alkyl  ethers 
(D.  R.  P.  249907). 

Diethylmalonamide  and  oxalyl  chloride  (D.  R.  PP. 
2254570,  227321). 


NARCOTICS  AND  GENERAL  ANESTHETICS    47 

Use  of  calcium  carbide  as  condensing  agent  (D.  R.  P. 

185963). 

Hydrolysis  of  thiobarbituric  acids  (dialkylmalonic  esters 
or  thiourea)  (D.  R.  P.  182764). 

Preparation  of  dialkylthiobarbituric  acids  (D.  R.  PP. 
234012,  235801). 

From  dialkyliminobarbituric  acid  (ex  guanidine  and 
dialkylmalonic  ester)  (D.  R.  P.  235802). 

Monoalkylbarbituric  acids  (urea  and  monoalkylmalonic 
esters)  (D.  R.  P.  146948). 

Ureides  of  dialkylacetic  acid,  by  treating  a  mixture  of 
dialkyl  malonic  acid  and  urea  with  fuming  H2SO4  and 
heating  the  product,  ureidodialkylmalonic  acid.  CO2  and 
dialkylacetyl  urea  result  (D.  R.  P.  144431). 

From  allophanic  esters  or  biuret  and  diethylmalonic 
ester  (D.  R.  P.  183857). 

Dialkylmalonhalides  and  allophanic  esters  (D.  R.  P. 
177694). 

From  dialkylmalonuric  acid  amide  (from  cyandialkyl 
acetyl  urea)  (D.  R.  P.  174178). 

From  halogen  substituted  iminodialkylpyrimidines 
(D.  R.  P.  217946). 

From  dialkylthiobarbituric  acids  (D.  R.  P.  179907). 

Disodio  cyanamide  as  condensation  medium  (D.  R.  P. 

178935). 

From  dialkylmalonicdiaryl  esters  and  guanidine  (D.  R.  P. 
231887). 

Dialkylmalonamic  esters  by  alkylation  of  malonamic 
esters  (D.  R.  P.  182045). 

BROMURAL  (a-Monobromoisovaleryl  urea) 

r— CO— NH— CO— NH2.     223. 

Two  parts  of  a-bromoisovaleryl  bromide  are  intimately 
mixed  with  i  part  of  perfectly  dry,  finely  powdered  urea. 
The  urea  passes  gradually  into  solution,  the  mixture  attaining, 
without  the  application  of  external  heat,  a  temperature  of 
about  70°.  It  is  maintained  at  this  temperature  until 


48  ORGANIC  MEDICINAL   CHEMICALS 

the  odour  of  the  acid  bromide  is  no  longer  perceptible,  for 
which  several  hours  are  required.  After  cooling,  the  mass 
is  powdered  and  treated  with  sodium  bicarbonate  solution, 
to  remove  hydrobromic  acid  and  some  a-bromisovaleric 
acid  which  is  formed.  The  product  is  then  dried  and  crystal- 
lised from  toluene,  from  which  it  separates  in  leaflets,  melting 
at  149°  (D.  R.  P.  185962). 

Colourless  tasteless  crystals,  sparingly  soluble  in  cold 
water,  easily  in  ether,  alcohol,  and  alkalis. 

Bromural  is  employed  as  a  hypnotic  in  nerve  cases,  and 
is  stated  not  to  possess  the  harmful  by-effects  of  veronal. 
It  is  claimed  that  sleep  is  produced  without  the  circulation 
or  respiration  being  markedly  affected.  It  does  not,  how- 
ever, bring  about  the  desired  effects  in  cases  of  insomnia 
in  which  pain,  cough,  angina  pectoris,  or  delirium  exists. 

NEURONAL  (Diethylbromoacetamide)  (C2H5)2CBrCONH2 
194. — Neuronal  is  prepared  (D.  R.  P.  158220)  by  dissolving 
bromodie  thy  lace  tyl  bromide  in  ether  and  passing  in  ammonia 
gas  to  saturation. 

(C2H5)2CBr— COBr+2NH3  ->  (C2H6)2CBrCONH2+NH4Br 

The  product  is  filtered  off,  washed  with  water  to  remove 
ammonium  bromide,  dried,  and  recrystallised  from  petroleum 
ether. 

Alternatively,  the  acid  halide  is  allowed  to  flow,  with 
cooling  and  stirring,  into  an  excess  of  aqueous  ammonia. 

A  colourless  crystalline  compound  containing  41  %  of 
bromine.  Sparingly  soluble  in  water. 

Neuronal  was  introduced  as  a  hypnotic  and  sedative,  and 
is  said  to  have  a  very  rapid  action  and  to  serve  well  in  condi- 
tions of  excitement  and  nervous  irritability.  It  has  no 
cumulative  effect  and  the  patient  does  not  become  habituated 
to  its  use,  but  it  is  said  to  cause  depression. 


SECTION  II. —NATURALLY    OCCURRING 
ALKALOIDS  AND  THEIR  DERIVATIVES 

NOTWITHSTANDING  the  many  rivals  to  morphine  which 
organic  chemistry  has  provided  of  late,  none  has  supplanted 
it.  For  its  value  in  allaying  pain,  morphine  is  probably 
still  to  be  regarded  as  superior  to  every  other  drug.  How- 
ever, the  danger  of  inducing  the  habit  of  taking  morphine 
and  the  other  disadvantages  of  its  use  are  serious  drawbacks, 
and  with  the  advance  of  knowledge  of  pharmacology  it  must 
be  regarded  as  probable  that  by  the  combined  use  of  anti- 
pyretic and  narcotic  synthetic  drugs,  morphine  and  its 
analogues  will  ultimately  be  replaced. 

As  the  methods  of  manufacture  of  the  different  alkaloids 
may  conveniently  be  considered  jointly,  the  present  section 
deals  with  the  alkaloids  in  common  use,  with  the  exception 
of  cocaine,  which  is  treated  separately  with  the  local 
anaesthetics  in  the  next  section. 

The  isolation  of  alkaloids  from  plant  materials  follows  to 
a  certain  extent  the  same  lines  whatever  the  nature  of  the 
alkaloid,  but  some  being  more  prone  to  hydrolysis  than 
others  require  expensive  low-boiling  solvents  for  their 
extraction ;  while  many,  as  for  instance  strychnine  and 
quinine,  may  be  boiled  with  water  with  relative  impunity, 
so  that  they  are  extracted  by  less  expensive  methods. 

Speaking  generally,  the  procedure  is  to  remove  by  means 
of  a  solvent  the  bases  present  in  the  plant,  leaving  the  sugar, 
starch,  protein,  and  pectenous  matter  unextr acted.  Fats, 
if  present,  accompany  the  bases ;  chlorophyll  may  or  may  not 
do  so,  according  to  the  solvent.  The  solvents  employed  are 
very  numerous ;  alcohol,  fusel  oil,  benzene,  solvent  naphtha, 
i.  49  4 


ORGANIC  MEDICINAL  CHEMICALS 


ether,  and  petroleum  being  variously  employed  according 
to  the  circumstances.  If  benzene,  solvent  naphtha,  or 
petroleum  is  used  it  is  necessary  to  set  free  the  bases  in 
the  plant  by  treatment  with  lime  or  alkali,  since  the  alkaloids 
are  present  in  combination  with  weak  acids  and  are  as  a 

rule  insoluble  in  this 
condition  in  these 
solvents.  Many  suit- 
able extraction  plants 
for  use  with  volatile 
solvents  have  been 
designed.  That  illus- 
trated in  Fig.  8,  by  the 
Standard  Chemical 
Engineering  Co.,  is 
economical  as  regards 
heat  consumption  and 
solvent  losses.  It  is 
constructed  on  the 
principle  of  the  well- 
known  Soxhlet  ex- 
traction, the  solvent 
refluxing  from  the 
condenser  into  the 
material  packed  in  the 
upper  part  of  the  lower 
vessel.  The  extract 
percolates  through 
into  the  lower  half  of 
this  vessel,  from  which 
it  is  vaporised  to  the 

FIG.  8.-Extraction  plant-Fischer  type.       Denser,  Caving  the 

extract. 

The  solvent  is  next  extracted  with  dilute  acid ;  in  some 
cases  it  is  unnecessary  first  to  distil  away  any  of  the  solvent, 
but  usually  the  greater  part  is  first  removed.  The  weak 
acid  extract  is  frequently  concentrated  in  vacuo'  before 
neutralisation,  and  thus  is  obtained  in  very  crude  form  the 


NATURALLY  OCCURRING  ALKALOIDS        51 

total  alkaloid  of  the  plant,  admixed  with  a  certain  amount 
of  sugar  and  so  forth.  Fat  is  removed  at  this  stage  by 
extraction  with  benzene  or  petroleum,  in  which  the  salts 
of  the  alkaloid  are  not  soluble.  The  further  treatment  and 
the  long  and  tedious  separation  and  purification  of  the 
alkaloids  must  be  varied  not  only  with  each  kind  of  material, 


Condenser 


Water 


FIG.  9. — Extraction  of  aqueous  liquids  with  light  solvents. 

but  with  every  batch,  and  requires  great  skill  and  experience 
and  extremely  careful  workers. 

For  the  extraction  of  an  aqueous  liquid  with  ether, 
petrol  or  other  light  immiscible  solvent  the  apparatus 
shown  in  Fig.  9  is  suitable.  The  liquid  to  be  extracted  is 
placed  in  A,  which  is  fitted  with  an  efficient  cooling  coil.  The 


ORGANIC  MEDICINAL  CHEMICALS 


vSolvent  enters  at  B  either  as  a  liquid  or  vapour  and  overflows 
into  the  still  C,  from  which  the  extract  is  finally  removed. 

MORPHINE  C17H19O3N.  285.— By  the  assiduous  work  of 
many  chemists  the  constitution  of  morphine  has  been  in  the 
main  elucidated ;  there  remains,  however,  a  choice  to  be 
made  between  several  formulae  which  explain  satisfactorily 
its  known  reactions.  Of  those  formulse,  the  two  following 
are  of  chief  importance  : 


H  N-CH3 


N'CH3 


OH! 


II 


H 


Knorr's  formula. 


O— CH  CIL, 

/\ 
H    OH 

Pschorr's  formula. 


Morphine  is  obtained  from  opium,  the  dried  latex  or 
sap  of  the  unripe  fruit  of  Papaver  somnifentm,  the  opium 
poppy,  which  is  cultivated  in  Asia  Minor,  Persia,  India,  and 
China.  Twenty -five  alkaloids  have  so  far  been  isolated  from 
opium,  the  most  important,  medicinally,  being  morphine, 
next  to  which  comes  codeine.  Smyrna  opium,  which 
comprises  the  bulk  of  that  employed  for  manufacturing 
purposes,  contains  9-12  %  of  morphine,  0*3-1 'o  %  of 
codeine,  and  4-6  %  of  narcotine.  The  recorded  alkaloidal 
content  of  India,  Persian,  and  Chinese  opium  is  as  follows  :— 


Opium. 

Per  cent,  morphine. 

Per  cent,  narcotine. 

Indian 
Persian 
Chinese 

3-2-8-6 
6-8 
4-3-11-2 

3-1-7-1 

5-7 
1-6-6-6 

1 

For  the  extraction  of  the  alkaloids  the  opium  is  worked 
down  to  a  thin  paste  with  calcium  chloride  solution  and  then 


NATURALLY  OCCURRING  ALKALOIDS        53 

extracted  with  warm  water.  By  this  treatment  the  morphine 
and  other  bases  are  converted  into  their  respective  hydro- 
chlorides,  whilst  the  acids  with  which  they  were  combined 
in  the  drug,  such  as  meconic  acid,  are  precipitated  as  insoluble 
calcium  salts.  The  insoluble  matter  is  separated  by  means 
of  a  filter  press  or  suction  filter,  and  to  prevent  oxidation 
sodium  sulphite  is  added  to  the  filtrate,  which  is  then  concen- 
trated, preferably  in  vacuo,  to  the  consistency  of  a  thin 
syrup.  Addition  is  then  made  of  a  concentrated  sodium 
acetate  solution,  which  precipitates  narcotine  and  papaverine. 
These  are  filtered  off,  a  small  proportion  of  alcohol  is  added 
and  the  morphine  is  precipitated  from  the  warmed  filtrate 
by  the  careful  addition  of  lime  in  presence  of  ammonium 
chloride  or  by  the  addition  of  caustic  soda.  It  is  allowed  to 
stand  and  is  removed  by  filtration.  The  filtrate  is  extracted, 
after  cooling,  with  benzene  or  chloroform,  whereby  codeine 
is  removed.  It  is  isolated  by  extraction  with  acid  and 
regenerating  and  crystallising  as  base  from  water. 

The  crude  morphine  is  freed  from  traces  of  codeine  by 
washing  it  with  benzene.  It  is  then  mixed  with  thrice  its 
weight  of  boiling  water  and  treated  with  the  exact  quantity 
of  25  %  hydrochloric  acid  required  for  neutralisation.  To 
prevent  atmospheric  oxidation  the  solution  is  covered  with 
a  layer  of  petroleum.  Morphine  hydrochloride  crystallises 
out  on  cooling,  is  filtered  off,  recrystallised  from  water  till 
pure,  and  dried  at  atmospheric  temperature.  From  an 
aqueous  solution  of  the  pure  hydrochloride,  pure  morphine 
may  be  obtained  by  precipitation  with  ammonia. 

Anhydrous  morphine  melts  at  230°.  It  is  soluble 
in  5000  parts  of  water  at  15°,  in  500  parts  at  100°,  in 
300  parts  of  cold  90  %  alcohol,  and  in  30  parts  of  boiling 
alcohol.  It  dissolves  in  200  parts  of  chloroform  and  is  only 
very  slightly  soluble  in  ether,  ethyl  acetate,  or  benzene. 

0-2  gram  of  morphine  should  form  a  clear  solution  in 
4  c.c.  of  caustic  potash  solution  (5  %  w/w).  A  solution 
of  O'i  gram  morphine  in  10  c.c.  of  10  %  hydrochloric  acid 
should  afford  no  red  coloration  with  ferric  chloride  solution 
(absence  of  meconates). 


54  ORGANIC  MEDICINAL  CHEMICALS 

Treated    with    concentrated    sulphuric    acid    morphine 
should  dissolve  to  a  colourless  solution. 


SAI/TS  OF  MORPHINE 

Morphine  hydrochloride  Ci7H19O3N'HCl  +  3H2O. 
375 '4- — White,  lustrous,  silky  needles.  Dissolves  in  24  parts 
of  water,  giving  a  neutral  solution.  It  should  contain 
75*5  %  °f  anhydrous  morphine.  It  may  best  be  crystallised 
from  water  or  dilute  alcohol ;  the  presence  of  ammonium 
sulphite  is  of  assistance  in  preventing  coloration. 

Morphine  Acetate  Ci7H19O3N,  CH3COOH+3H2O.  399. 
— For  the  preparation  of  this  salt  10  parts  of  pure  powdered 
morphine  are  mixed  with  30  parts  of  hot  water  and  7  parts 
of  30  %  acetic  acid.  The  solution  is  filtered  hot  and  evapo- 
rated in  vacuo  at  50°  to  20  parts.  It  is  cooled,  seeded  with 
a  crystal  of  morphine  acetate  and  kept  in  a  cold  place. 
Access  of  air  should  be  prevented,  by  a  layer  of  petroleum 
or  by  other  means.  Morphine  acetate  crystallises  out  and 
is  dried  at  atmospheric  temperature. 

A  light,  white,  crystalline  powder.  Dissolves  in  3  parts 
of  water  to  a  solution  which  becomes  perfectly  clear  on 
addition  of  a  small  quantity  of  acetic  acid.  To  obtain  the 
salt  completely  soluble  in  water  it  is  necessary  to  crystallise 
it  from  a  slight  excess  of  acetic  acid  and  to  dry  with  great 
caution. 

Morphine  acetate  should  contain  at  least  71  %  of 
morphine. 

Morphine  Sulphate  (C17H19O3N)2,  H2SO4+5H2O.  758. 
—Forms  colourless  acicular  crystals,  soluble  in  21  parts 
of  water.  It  is  prepared  in  the  same  way  as  morphine 
hydrochloride  and  is  crystallised  from  water  in  the  presence 
of  ammonium  sulphite. 

Morphine  Tartrate  (Ci7H19O3N)2,  C4H6O6+3H2O,  774, 
is  prepared  by  dissolving  morphine  in  the  theoretical  quantity 
of  tartaric  acid  in  water,  from  which  it  separates  on  cooling 
as  a  white  crystalline  powder,  soluble  in  10  parts  of  water. 
Excess  of  tartaric  acid  must  be  avoided  because  the  acid 


NATURALLY  OCCURRING  ALKALOIDS        55 

tartrate  which  is  then  produced  is  sparingly  soluble  and 
separates  with  the  neutral  tartrate  on  cooling. 

Morphine  possesses  the  power  simultaneously  to  exercise 
a  depressant,  narcotic  action  on  the  brain  and  a  stimulating 
action  on  the  spinal  cord.  It  is  also  analgesic,  slows  the 
respiration,  but  has  little  effect  on  the  circulation. 

It  is  widely  employed  as  an  hypnotic,  being  usually 
administered  by  hypodermic  injection  of  one  of  its  salts. 
Morphine  acts  more  quickly  than  opium,  and  is  less  likely 
to  disturb  the  digestion  or  to  cause  headache  and  nausea. 

Codeine  C18H21O3N.    299.— 
H 


CH30V  A  A  /1CH2  CH30 

,       r-  Or 

O— \/ 

HOH  C 

HOH 

Knorr's  formula.  Pschorr's  formula. 

Codeine  is  a  methyl  ether  of  morphine.  It  occurs  in 
opium  in  amounts  varying  fromo 'I  %  to  3-0  %  and  is  isolated 
therefrom  in  the  way  already  described  (see  Morphine). 

Much  of  the  codeine  of  commerce,  however,  is  prepared 
synthetically  by  the  methylation  of  morphine. 

The  following  methylating  agents  have  been  proposed  : 

Methyl  iodide  (Compt.  Rend.  92,  1140,  1228  ;  93,  67, 

217,  591)- 

Salts  of  methyl  sulphuric  acid  (D.  R.  P.  39887). 

Nitrosomethyl  urethane,  or  diazome thane,  (D.  R.  PP. 
92789,  95644,  96145). 

Dimethyl  sulphate  (D.  R.  P.  102634). 

Methyl  phosphate  (D.  R.  P.  107225). 

Methyl  nitrate  (D.  R.  P.  108075). 

^-toluene  sulphon  nitrosomethyl  amide  (D.  R.  P.  224388). 

Methyl  sulphite  (D.  R.  P.  214783). 

Methyl  benzene  (or  toluene),  sulphonate  (D.  R.  P. 
131980). 


56          ORGANIC  MEDICINAL  CHEMICALS 

(1)  Employing  Dimethyl  Sulphate  (D.  R.   P.  102634).— 
Morphine,  100  parts,  is  dissolved  in  a  solution  of  87  parts 
of  sodium  in  700  parts  of  methyl  alcohol,  and  the  solution 
treated  with   41*6  parts  of   dimethyl  sulphate    and  gently 
warmed.      Sodium  methyl  sulphate  separates,   and  is  fil- 
tered off.      The  filtrate  is  freed    from  methyl  alcohol  by 
distillation,  the  residue  dissolved  in  water,  made  alkaline 
with  ammonia,   and   the  codeine  extracted  with  benzene, 
from  the  solution  in  which  it  is  obtained,  after  removal  of 
the  bulk  of  the  solvent,  in  small  glistening  crystals. 

(2)  From  Nitroso  Methyl  Ur  ethane.  —  A  33  %  aqueous 
methylamine  solution  is  reacted  in  the  cold  with  methyl  (or 
ethyl)  chloroformate. 


The  reaction  mixture  is  extracted  with  ether,  and  the 
extract  distilled.  B.p.  158°.  On  treatment  with  sodium 
nitrite  and  sulphuric  acid,  nitroso  methyl  urethane 


NO 


co<; 


N— CH3 
OCH3 


is  formed  (R.  Trav.  Chim.  7,  353 ;  9,  139),  and  is  extracted 
with  ether. 

According  to  D.  R.  P.  95644,  285  grams  of  morphine 
and  132  grams  of  nitroso  methyl  urethane  are  dissolved  in 
1000  grams  of  methyl  alcohol.  With  stirring,  a  solution  of 
50  grams  of  KOH  in  800  grams  of  methyl  alcohol  is  slowly 
added.  The  methyl  alcohol  is  then  distilled  off,  and  the 
codeine  extracted  from  the  residue  with  benzol  and  purified 
by  recrystallisation. 

(3)  From  Diazomethane. — Diazomethane  is  prepared  by 
warming  i  volume  of  nitroso  methyl  urethane  with  i'2 
volumes  of  a  25  %  solution  of  KOH  in  methyl  alcohol  (Ber. 
27,  1888 ;  28,  856),  and  is  evolved  in  the  form  of  a  yellow 
gas,  which  is  absorbed  in  dry  ether.  It  can  also  be  made  from 


NATURALLY  OCCURRING  ALKALOIDS       57 

^-nitrophenylnitrosomethylamine  NO2\     J>N — CH3,  which 

NO 

decomposes,  on   treatment  with  alkali,  into  diazomethane 
and  sodium  _/>-nitrophenate. 

Morphine,  i  molecule,  dissolved  in  absolute  methyl 
alcohol,  is  allowed  to  flow  into  a  cooled  ethereal  solution  of 
diazo  methane.  When  evolution  of  nitrogen  has  ceased, 
and  the  colour  has  disappeared,  the  solvent  is  distilled  off 
and  the  codeine  purified.  (D.  R.  P.  92789.) 

N 
C17H1802N-OH+CH2/||  ->  C17H1802N-OCH3+N2 

XN 

Codeine  forms  small  glistening  crystals;  m.p.  155°. 
Soluble  in  80  parts  of  cold,  and  in  24  parts  of  boiling, 
water ;  in  12  parts  of  benzene,  2  parts  of  chloroform,  58 
parts  of  ether,  and  in  2  parts  of  90  %  alcohol. 

Codeine  should  dissolve  without  colour  formation  in  cold 
concentrated  sulphuric  acid.  A  saturated  aqueous  solution 
should  not  be  coloured  blue  by  ferric  chloride,  and  should 
gradually  afford,  on  acidification  with  hydrochloric  acid 
and  treatment  with  ferric  chloride  and  dilute  potassium 
ferricyanide,  only  a  dirty  green,  but  no  blue,  colour 
(absence  of  morphine). 

Codeine  Phosphate  C18H21O3N'H3PO4-}-2H2O.  433.— 
Codeine  phosphate  is  the  most  soluble  salt  of  codeine  and 
is  the  form  in  which  the  alkaloid  is  most  usually  administered. 
It  is  prepared  by  neutralising  codeine  with  the  calculated 
quantity  of  25  %  phosphoric  acid  and  adding  90  %  alcohol 
to  the  solution,  when  the  phosphate  is  precipitated  as  a  white 
crystalline  powder. 

Codeine  phosphate  dissolves  in  4  parts  of  water  at  ordinary 
temperature  and  in  200  parts  of  90  %  alcohol.  The  aqueous 
solution  possesses  a  feebly  acid  reaction  to  litmus.  It  should 
answer  the  tests  prescribed  for  codeine. 

Codeine  is  used  to  stop,  or  lessen,  glycosuria  in  diabetes  ; 
in  the  treatment  of  irritant  coughs;  for  abdominal  and 
ovarian  pain,  and  as  a  mild  hypnotic. 


58  ORGANIC  MEDICINAL    CHEMICALS 

Codeine  Hydrochloride  C18H21O3N-HC1-2H2O,  371  -4, 
forms  a  white  crystalline  powder  soluble  in  20  parts  of  water. 

Codeine  Sulphate  (C18H21O3N)2H2SO45H2O,  678-6, 
may  be  obtained  in  fine  needles  by  crystallisation  from  water, 
in  which  it  is  very  soluble.  It  readily  loses  its  water  of 
crystallisation. 

APOMORPHINE  Ci7H17O2N.     267. 

OH 


Apomorphine  is  derived  from  morphine  by  abstraction 
of  the  elements  of  water. 

The  best  published  method  of  preparation  is  still  that  of 
the  discoverers  of  this  substance  (Matthieson  &  Wright, 
Annalen,  1870,  Suppl.  7,  170,  177),  but  by  it  very  indifferent 
yields  may  be  obtained. 

Morphine,  i  part,  is  heated  under  pressure  with  10  parts 
of  25  %  HC1  for  2-3  hours  at  I40°-i5o°.  When  cold, 
the  solution  is  treated  with  a  slight  excess  of  sodium  bicar- 
bonate, and  extracted  with  ether,  benzene  or  chloroform, 
air  being  excluded.  The  apomorphine  is  obtained,  as 
hydrochloride,  when  the  resulting  solution  is  agitated  with 
concentrated  hydrochloric  acid,  and  the  salt  is  purified  by 
recrystallisation  from  water. 

Apomorphine  hydrochloride  C17H17NO2'HC1JH2O,  occurs 
as  small  white  or  greyish-white  needle-shaped  crystals, 
soluble  in  60  parts  of  cold  water  and  in  50  parts  of  alcohol, 
90  %.  On  exposure  to  air  and  light  it  turns  green. 

The  aqueous  solution  (i  :  100)  should  be  neutral  to  litmus, 
or  only  faintly  acid,  and  almost  colourless.  Apomorphine 
hydrochloride  is  soluble  in  5  parts  of  alcohol.  !  It  is  a  non- 
irritant  emetic  and  is  the  most  reliable  drug  known  for  this 
purpose.  It  is  usually  administered  hypodermically,  but 
may  be  given  by  the  mouth  also.  It  takes  effect  promptly 


NATURALLY  OCCURRING  ALKALOIDS        59 

(2  or  3  minutes)  without  production  of  much  preceding 
nausea  or  unpleasant  by-effects.  It  acts  as  a  stimulant  of 
the  central  nervous  system,  particularly  of  the  vomiting 
centre  of  the  medulla  oblongata. 

NARCOTINE  C22H23O7N.  413.  —  The  mixture  of  narcotine 
and  papaverine  precipitated  by  sodium  acetate  from  the 
solution  of  the  hydrochlorides  of  the  mixed  alkaloids  from 
opium  (see  Morphine)  is  treated  with  oxalic  acid  solution 
in  sufficient  quantity  to  form  the  acid  oxalates.  Narcotine 
acid  oxalate  dissolves,  papaverine  acid  oxalate  remains  mostly 
undissolved  and  is  filtered  off.  The  narcotine  is  precipitated 
from  the  nitrate  by  ammonia  and  is  purified  by  recrystallisa- 
tion  of  the  alkaloid  from  alcohol. 

Colourless  needles;  m.p.  176°.  Insoluble  in  water, 
soluble  in  100  parts  of  cold  alcohol,  in  170  parts  of  ether, 
and  in  22  parts  of  benzene.  Readily  soluble  in  chloroform 
and  in  hot  alcohol.  Narcotine  possesses  no  narcotic 
properties  ;  it  is  little  used  in  medicine,  but  is  sometimes 
given  as  a  substitute  for  quinine,  as  an  antiperiodic  in  ague. 

It  is  employed  for  the  preparation  of  cotarnine,  which 
it  affords  on  oxidation. 

COTARNINE  C12H15O4N.     239. 


CH2-NH-CH3 

CHO 


OCH 


Cotarnine  is  obtained  by  oxidising  narcotine  with  nitric 
acid,  opianic  acid  being  produced  at  the  same  time  (Ander- 
son, Ann.  86,  187(1853)).  One  part  of  narcotine  is  dissolved 
in  8  parts  of  water  and  2'8  parts  of  nitric  acid  (sp.gr.  1-4) 
and  the  mixture  warmed  to  49°.  When  nitrous  fumes  have 
ceased  to  be  evolved,  the  solution  is  cooled  and  filtered  ; 
the  cotarnine  is  precipitated  by  the  addition  of  caustic  alkali 
solution,  and  purified  by  recrystallisation  from  benzene, 
or  by  conversion  into  the  hydrochloride.  (Ann.  86,  187.) 

Small  needles,  m.p.  132°,  readily  soluble  in  alcohol  or 
ether,  sparingly  soluble  in  water. 


60  ORGANIC  MEDICINAL   CHEMICALS 

Cotarnine  Hydrochloride  C12HUO3NC1  +  2H2O,  is 
employed  in  medicine  under  the  name  "  Stypticine." 

A  pale  yellow,  crystalline  powder,  soluble  in  water  and 
alcohol.  It  is  used  as  an  internal  styptic,  principally  for 
arresting  uterine  haemorrhage.  It  acts  directly  on  the 
uterus,  causing  contraction. 

Cotarnine  Phthalate,  employed  for  the  same  purpose, 
is  known  as  "  Styptol." 

HYDRASTINE  C21H21O6N.     383. 

CH  CH2 

O—  C/ 
CH2< 


CH  CH 
CH— O 

C 

HC/^C'CO 


COCH3 

Hydrastine  is  prepared  from  the  root  of  Hydrastis 
Canadensis,  or  Golden  Seal,  a  plant  which  is  indigenous  to 
North  America  and  is  to  a  small  extent  cultivated  there. 
The  dried  rhizomes  and  rootlets  contain  2*5  to  4*0  %  of 
hydrastine,  3-4  %  of  berberine,  and  a  small  quantity  of 
canadine.  The  powdered  root  is  extracted  exhaustively 
with  hot  water,  acidified  with  acetic  acid,  or  with  alcohol. 
The  extract  is  evaporated  in  vacuo  to  a  thin  syrup.  Two 
to  three  volumes  of  20  %  sulphuric  acid  are  added,  when 
crystalline  berberine  acid  sulphate  separates.  The  crude 
sulphate  is  filtered  off  and  dissolved  in  the  minimum  quantity 
of  boiling  water  ;  the  hot  solution  is  mixed  with  an  equal 
volume  of  alcohol,  and  concentrated  sulphuric  acid  to  the 
amount  of  1/50  th  the  volume  of  the  solution  is  added. 
Berberine  acid  sulphate  C2oH17O4N-H2SO4  crystallises 
out  and  is  filtered  off.  The  filtrates  from  the  berberine 


NATURALLY  OCCURRING  ALKALOIDS         61 

sulphate  are  freed  from  alcohol  and  made  alkaline  with 
ammonia,  when  hydrastine  is  precipitated.  This  is  filtered 
off  and  purified  by  crystallisation,  first  from  ethyl  acetate 
and  then  from  a  mixture  of  chloroform  and  alcohol.  The 
alkaloid  when  pure  melts  at  133°  and  is  colourless ;  a 
yellow  colour  usually  indicates  the  presence  of  canadine  or 
berberine,  but  the  last  trace  of  colour  can  only  be  removed 
by  repeated  purification. 

An  alternative  method  of  removing  berberine  is  to  dissolve 
the  alkaloid  in  ether  or  toluene,  filter  off  the  insoluble  berberine 
and  subsequently  to  extract  the  base  from  the  solvent  with 
dilute  acid. 

Hydrastine  acid  oxalate  and  hydrastine  acid  tartrate 
may  be  recrystallised  from  hot  water,  and  being  but  sparingly 
soluble  in  cold  water  they  may  usefully  be  employed  in 
alternative  methods  of  purification,  especially  for  the 
removal  of  canadine,  which  is  apt  to  remain  associated  with 
hydrastine. 

Hydrastine  Hydrochloride  C2iH21O6N'HCl,  419-4^  is 
prepared  by  passing  dry  hydrochloric  acid  gas  into  an 
ethereal  solution  of  the  base,  or  by  drying  down  an  alcoholic 
solution  of  the  salt  obtained  by  neutralisation. 

Hydrastine  hydrochloride  is  a  white  or  very  pale  yellow 
hygroscopic  crystalline  powder,  melting  at  116°,  readily 
soluble  in  water,  alcohol  and  in  chloroform. 

Hydrastine  is  poisonous  in  large  doses.  It  resembles 
strychnine  in  increasing  reflex  irritability.  If  injected  it 
causes  contraction  of  the  uterus,  and  has  been  used  as  an 
ecbolic  to  induce  premature  labour.  See,  Ber.  (1886),  19, 
2798;  C.  &  D.  (1901),  59, 152;  Arch.  Pharm.  (1888),  226, 329. 

HYDRASTININE  CnH^C^N.     207. 


CH/ 


CH   CH2 

Hydrastinine  does  not  occur  naturally,  but  is  prepared 
by  the  oxidation  of  hydrastine,  or  from  narcotine  through 
cotarnine. 


62  ORGANIC  MEDICINAL  CHEMICALS 

From  Hydmstine.  —  Hydrastinine  is  obtained  from  hydras- 
tine  as  follows  (Ber.  (1887),  20,  88)  :—  10  parts  of  hydrastine 
are  heated  with  a  mixture  of  25  parts  of  water  and  50  parts 
by  vol.  of  nitric  acid  (sp.gr.  1-3),  at  5o°-6o°,  until  a  test- 
portion  ho  longer  gives  a  precipitate  when  treated  with 
ammonia.  The  solution  is  then  cooled,  made  slightly 
alkaline  with  caustic  alkali,  the  hydrastinine  extracted  with 
chloroform  or  with  ether,  and  the  solvent  removed.  The 
base  is  then  recrystallised  from  light  petroleum  and  ether. 

The  hydrochloride  is  prepared  by  neutralising  an 
alcoholic  solution  of  the  base  with  hydrochloric  acid  and 
may  be  crystallised  from  alcohol. 

From  Narcotine.  —  Cotarnine  is  first  prepared  (see  method 
given  on  page  59)  and  is  reduced  to  hydrocotarnine  by 
adding  sodium  amalgam  to  a  solution  of  the  base  in  dilute 
hydrochloric  acid.  The  reaction  proceeds  almost  quanti- 
tatively (Ber.  24,  2734). 

CH3O 

/0/\/CHO 

\      I       I 

X0\ACH2/ 

Cotarnine. 

CH3O      CH2  CH 


CH2  CH2 

Hydrocotarnine.  Hydrohydrastinine. 

HYDROHYDRASTININE  is  prepared  from  hydrocotarnine 
according  to  the  method  of  Pyman  and  Remfry  (Trans. 
J.  Chem.  Soc.  101,  1601)  :  120  parts  of  crude  hydrocotarnine 
are  dissolved  in  450  volumes  of  dry  fusel  oil  (b.p. 
I22°-I32°).  To  one-third  of  the  solution,  heated  to  boiling, 
are  added  180  parts  of  sodium.  When  this  has  melted  the 
remainder  of  the  solution  is  added  in  the  course  of  20  minutes, 
when  the  temperature  rises  to  i55°-i6o°.  Dry  fusel  oil, 
2500  parts,  is  run  in,  in  a  constant  stream,  in  the  course  of 
100  minutes,  by  which  time  nearly  all  the  sodium  has 
dissolved.  The  solution  is  then  cooled,  separated  from 
unchanged  sodium,  and  washed  with  dilute  caustic  soda  to 


NATURALLY  OCCURRING  ALKALOIDS         63 

remove  phenolic  bases.  The  hydrocotarnine  is  then  extracted 
with  hydrochloric  acid,  the  acid  solution  made  alkaline  and 
shaken  out  with  chloroform.  After  removal  of  the  solvent 
the  residue  is  dissolved  in  300  parts  of  alcohol  and  the  solution 
made  slightly  acid  by  addition  of  30  %  hydrobromic  acid. 
On  standing,  65-70  parts  of  hydrohydrastinine  hydrobromide 
crystallise  out. 

Hydrohydrastinine  is  then  treated  in  dilute  sulphuric 
acid  solution  with  a  solution  of  potassium  bichromate  and 
thus  oxidised  to  hydrastinine  (Ber.  (1887),  2O,  2403). 

Another  synthesis  of  hydrastinine  is  described  by  Decker 
(D.  R.  P.  234850).  Homopiperonylamine  is  converted  to 
its  formyl  derivative  which,  when  heated  with  phosphoric 
oxide,  yields  6  :  7-methylenedioxy-3  :  4-dihydro  iso  quinoline. 
The  latter  on  treatment  with  methyl  iodide  gives  hydrastinine. 


. 

Methylenedioxy-w-mtrostyrol  CH2\ 

a  condensation  product  of  piperonal  and  nitromethane, 
75  parts,  is  dissolved  in  a  mixture  of  300  parts  of  alcohol 
and  300  parts  of  acetic  acid.  Zinc  dust,  150  parts,  is 
gradually  added,  and  after  reduction  is  complete  the  zinc  is 
filtered  off.  The  filtrate  is  treated  with  a  further  quantity,  600 
parts,  of  a  mixture  of  equal  volumes  of  alcohol  and  acetic 
acid,  and  then,  gradually,  with  1800  parts  of  4  %  sodium 
amalgam.  After  cooling,  800  parts  of  water  are  added, 
and  unchanged  homopiperonal-oxime  allowed  to  crystallise 
out.  The  filtrate  from  this  is  made  alkaline  with  caustic  soda 
and  the  base  (homopiperonylamine)  extracted  with  a  solvent 
and  distilled.  B.p.  145°  at  17  mm.  (D.  R.  P.  245523). 

From  this  is  prepared  formyl  homopiperonylamine 
(Ber.  41,  2752)  by  heating  the  formate  at  i6o°-i70°. 

To  obtain  hydrastinine,  10  parts  of  formyl  homopiperonyl- 
amine are  dissolved  in  70  parts  of  toluol  and  boiled  with 
15  parts  of  phosphorus  pentoxide.  The  resulting  insoluble 
CH 


product,  CH2\Q|    J      |QJJ  ,  is  filtered  off,  dissolved  in  40 
CH, 


64  ORGANIC  MEDICINAL  CHEMICALS 

parts  of  xylene  and  boiled  with  8  parts  of  dimethyl  sulphate. 
On  cooling,  hydrastinine  methyl  sulphate  separates.   (D.  R.  P. 

234850.) 

A  further  partial  synthesis  has  been  effected,  employ- 
ing berberine  as  the  initial  material  (D.  R.  P.  241136). 
Benzyldihydroberberine,  prepared  (D.  R.  P.  179212)  from 
berberine  chloride  and  benzyl  magnesium  bromide,  50  parts, 
is  dissolved  in  300  volumes  of  alcohol  and  350  volumes  of 
concentrated  hydrochloric  acid.  The  solution  is  boiled,  and 
treated  with  150-200  parts  of  tinfoil.  Heating  is  continued 
for  5-10  hours,  whereupon  the  tin  double  salt  of  the  resulting 
base,  benzyltetrahydroberberine,  separates.  This  is  filtered 
off  and  digested  with  ammonium  sulphide  solution  in  excess. 
The  undissolved  base  is  filtered  off,  dried,  and  extracted 
with  chloroform.  (M.p.  i63°-i65°.) 

Benzyltetrahydroberberine,  100  parts,  is  heated  with 
100  volumes  of  methyl  iodide,  for  4-5  hours  at  100°.  The 
methiodide  which  results  is  washed  with  alcohol,  added 
(60  parts)  to  200  volumes  of  50  %  alcohol  in  which  40  parts 
of  freshly  precipitated  silver  oxide  are  suspended.  After 
digestion  at  50°  for  a  half -hour  the  silver  iodide  is  filtered  off, 
the  solution  concentrated  till  an  oil  separates,  treated  with 
35  parts  of  "  stick "  potash,  and  boiled  for  some  time. 
After  cooling,  the  crystalline  product  is  filtered  off,  washed 
with  cold  alcohol  and  recrystallised  from  this  solvent. 

(M.p.  I2I°-I22°.) 

The  base  (2  parts)  is  dissolved  in  4  volumes  of  glacial 
acetic  acid  which  has  been  distilled  over  sodium  bichromate, 
and  a  solution  of  1*5  parts  of  this  salt  in  15  volumes  of  50  % 
acetic  acid  added  at  once.  The  mixture  is  kept  at  90°  for 
2  hours,  or  until  completely  green.  After  addition  of  a 
little  alcohol  to  complete  reduction  of  the  bichromate,  water 
is  added,  and  sodium  carbonate  until  alkaline.  A  reddish 
gum  separates  and  is  removed.  On  heating,  chromium 
oxide  is  precipitated,  and  is  filtered  off.  The  filtrate  is  made 
strongly  alkaline  with  caustic  soda  and  the  hydrastinine 
extracted  with  ether,  from  which  it  is  subsequently  obtained 
by  evaporation.  The  yield  is  said  to  be  78  %. 


NATURALLY  OCCURRING  ALKALOIDS        65 

Hydrastinine  forms  white  crystals  (m.p.  117°)  which  are 
readily  soluble  in  alcohol,  ether,  benzene  and  light  petroleum  : 
they  dissolve  in  water  to  form  an  alkaline  solution  which 
is  fluorescent. 

Hydrastinine  hydrochloride  is  the  salt  employed  hi 
medicine,  and  forms  faintly  yellow  needles  readily  soluble 
in  water  and  showing  a  blue  fluorescence  in  dilute  solution. 

It  exerts  a  powerful  action  on  the  uterus,  causing  rhythmic 
contraction,  and  for  this  purpose  is  to  be  regarded  as  of 
greater  value  than  hydrastine. 

EMETINE  C29H40O4N2.  480.— The  chief  source  of 
emetine  is  the  root  of  Psychotria  Ipecacuanha,  a  plant 
indigenous  to  South  America  and  cultivated  in  Selangor, 
Federated  Malay  States.  The  root  from  the  latter 
source  is  known  as  "  Johore "  ipecacuanha ;  that  from 
Brazil  is  marketed  under  the  names  of  "  Rio/'  "  Matto 
Grosso,"  or  "Minas,"  whilst  from  Colombia  is  derived 
another  species  of  ipecacuanha,  Psychotria  acuminata, 
the  root  of  which  is  commonly  sold  as  Carthagena  ipecac- 
uanha. Brazilian  and  Johore  roots  contain  up  to  2*5  % 
of  total  alkaloids,  in  the  ratio,  approximately,  of  emetine 
72,  cephaeline  26,  and  psychotrine  2  ;  whilst  Carthagena 
ipecacuanha  contains  up  to  2*0  %  of  alkaloid  in  the 
proportion — emetine  40,  cephseline  57,  and  psychotrine  3. 
Two  other  alkaloids  have  been  found  in  ipecacuanha,  emeta- 
mine  and  psychotrine  O-methylether. 

For  the  preparation  of  emetine  the  Brazilian  or  Johore 
root  is  preferably  employed.  The  drug  is  thoroughly 
powdered  and  extracted  with  hot  alcohol.  The  later  stages 
of  the  extraction  proceed  only  slowly  and  may  be  accelerated 
by  a  very  cautious  addition  of  alkali.  When  the  root  has 
been  exhausted,  the  combined  alcoholic  extracts  are  acidified 
with  hydrochloric  acid,  and  the  alcohol  distilled  off.  The 
residue  is  diluted  with  water,  filtered  from  fat,  etc.,  and  made 
alkaline  with  ammonia ;  the  alkaloids  are  then  extracted  with 
chloroform  or  ether.  Before  the  removal  of  the  solvent  the 
extract  is  freed  from  cephaeline  by  treatment  with  caustic 
soda  solution,  in  which  it  is  soluble.  The  remaining  emetine 

*•  5 


66          ORGANIC  MEDICINAL  CHEMICALS 

is  extracted  with  hydrobromic  acid  and  purified  by  recrystal- 
lisation  in  the  form  of  hydrobromide  and  as  hydrochloride 
from  water.  Emetine  base  cannot  be  crystallised ;  it  is 
readily  soluble  in  alcohol,  ether,  acetone  and  chloroform, 
less  so  in  benzene  or  petroleum.  When  dry  the  amorphous 
base  melts  at  74°. 

Emetine  Hydrobromide  C29H40O4N2'2HBr+4H2O, 
714,  crystallises  in  long  slender  needles  sparingly  soluble  in 
water  and  less  soluble  in  dilute  hydrobromic  acid.  It  has 
not  a  characteristic  melting  point,  but  fuses  between  245° 
and  265°. 

Emetine  Hydrochloride  C29H40O4N2-2HCl7H2O,  679, 
crystallises  in  white  powdery  needles,  soluble  in  8  parts 
of  water  at  18°,  less  soluble  in  the  presence  of  free  hydro- 
chloric acid.  Soluble  in  alcohol  and  chloroform.  It  has 
not  a  characteristic  melting  point,  but  melts  between  235° 
and  255°. 

Preparation  of  Emetine  from  Cephceline. — Cephaeline  not 
being  of  use  in  medicine,  may  be  utilised  for  the  preparation 
of  a  further  quantity  of  emetine  by  the  process  of  methylation. 
The  cephseline  is  recovered  as  alkaloid  from  the  caustic 
soda  solution  which  results  from  the  purification  of  emetine 
as  described  above.  For  this  purpose  sodium  bicarbonate 
is  added  and  the  mixture  extracted  with  chloroform.  The 
residue,  after  removing  chloroform  by  distillation,  is  dissolved 
in  hydrochloric  acid,  5  %,  and  allowed  to  crystallise  ;  the 
cephseline  hydrochloride  is  then  filtered  off  and  converted 
to  base  with  sodium  carbonate  and  extracted  with  chloro- 
form. The  dried  chloroform  extract  is  dissolved  (Fig.  10), 
in  a  solution  of  ^th  its  weight  of  sodium  in  10  times  its 
weight  of  dry  fusel  oil  (boiling  at  I3O°-I40°),  T40ths  its  weight 
of  anhydrous  sodium  methyl  sulphate  is  then  added  and  the 
mixture  boiled  under  a  reflux  condenser  for  two  hours.  By 
extracting  the  fusel  oil  with  dilute  hydrochloric  acid,  emetine 
and  unchanged  cephaeline  are  obtained  as  hydrochlorides 
and  are  separated  as  described  above.  (/.  Chem.  Soc.,  1913, 
1620.)  (Eng.  Pats.  14677  and  17483.) 

The  methylation  of  cephseline  may  also  be  conveniently 


NATURALLY  OCCURRING  ALKALOIDS 


67 


effected  by  the  use   of   nascent  diazo-methane  (D.  R.  P. 
298678). 

Emetine  has  a  strong  local  constricting  effect  upon  blood 

rn 


T 

^  —  rrr- 

m 

*& 

FIG.  10. — Reaction  vessel  for  alkylation. 

vessels  and  powerful  irritant  action  when  taken  internally, 
promoting  copious  salivary  secretion  and  vomiting.     It  is 


68  ORGANIC  MEDICINAL  CHEMICALS 

employed  as  expectorant  and  emetic.  It  has  a  wider 
application  in  the  treatment  of  amoebic  dysentery,  for  which 
purpose  the  hydrobromide  or  hydrochloride  may  be  injected 
hypodermically,  or  the  insoluble  double  bismuth  iodide 
may  be  administered  internally. 

HYOSCYAMINE  AND  ATROPINE  C17H23O3N.     289. 

CH2— CH-      -CH2 


N— CH3 

CH2— CH-      -CH2 

Atropine  is  the  optically  inactive  mixture  of  dextro-  and 
laevo-hyoscyamine.  L,3evo-hyoscyamine  alone  occurs  in 
nature.  The  best  source  of  hyoscyamine  is  a  variety  of 
henbane  indigenous  in  Egypt,  Soudan  and  India,  known  as 
Hyoscyamus  muticus,  in  the  various  parts  of  which  it  has 
been  shown  to  be  present  in  the  following  proportions: 
leaves  1-4  %  ;  stems  0*6  %  ;  seeds  0-87-1-34  %.  Atropine 
is  also  manufactured  from  the  root  of  Scopolia  carniolica, 
in  which  hyoscyamine  is  present  to  the  extent  of  0-43-0-51  %  ; 
and  from  Atropa  belladonna,  the  leaves  of  which  contain, 
on  the  average,  0*4  %,  and  the  roots  0*5  %,  of  hyoscyamine. 
Many  other  solanaceous  plants  of  the  Datura  species  contain 
these  alkaloids,  in  varying,  and  smaller,  amounts,  often 
associated  with  hyoscine  or  scopolamine. 

The  drug  should  be  dried  immediately  after  collection 
and  should  be  extracted  as  soon  as  possible,  as  the  alkaloid 
content  gradually  diminishes  on  keeping. 

For  the  manufacture  of  atropine  and  hyoscyamine  the 
drug  is  powdered  and  extracted,  in  a  copper  extractor,  by 
percolation  with  hot  alcohol  (S.V.M.),  until  free  from  alkaloid. 
The  alcohol  is  removed  from  the  extract  by  distillation, 
preferably  under  somewhat  diminished  pressure,  and  the 
syrupy  extract  is  allowed  to  flow,  in  a  thin  stream,  and  with 
good  stirring,  into  very  dilute  (0*5-1-0  %)  acid,  hydrochloric 
or  sulphuric.  The  aqueous  portion  is  separated  from  undis- 
solved  resinous  matter,  etc.,  and  is  further  freed  from  impurity 
by  being  shaken  out  with  petrol.  It  is  then  made  neutral, 


NATURALLY  OCCURRING  ALKALOIDS         69 

or  faintly  alkaline,  by  addition  of  ammonia  solution,  and  set 
aside  for  a  time,  when  a  quantity  of  resinous  material  is 
precipitated  and  removed.  An  excess  of  ammonia  is  then 
added,  whereby  the  alkaloids  are  precipitated.  They  are 
extracted  by  shaking  out  with  chloroform,  and  are  finally 
freed  from  resinous  and  other  impurity  by  being  dissolved 
out  of  the  chloroform  extract  with  dilute  acid,  reprecipitated 
with  ammonia,  and  again  extracted  into  chloroform.  The 
solvent  is  removed  by  distillation ;  and  the  treatment  of  the 
mixed  alkaloids,  consisting  mainly  of  /-hyoscyamine,  with  a 
little  atropine,  and  possibly  hyoscine,  varies  as  hyoscyamine 
or  atropine  is  required. 

The  alkaloid  is  converted  b)r  neutralisation  with  the 
required  quantity  of  oxalic  acid  into  the  oxalate  (B)  2H2C2O4 
(see  Trans.  Chem.  Soc.  (1912),  IOI,  946). 

This  is  recrystallised  from  water  until  it  has  the  melting 
point  of  pure  /-hyoscyamine  oxalate  (176°).  The  base  is 
then  obtained  by  dissolving  the  oxalate  in  water,  making 
alkaline  with  ammonia  and  extracting  with  chloroform. 
After  removing  the  solvent,  the  neutral  sulphate  is  prepared 
and  crystallised  from  alcohol  or  moist  acetone. 

Lsevo-Hyoscyamine  Sulphate 

(C17H2303N)2H2S04+2H20.    712. 

White,  slender,  hygroscopic  needles.  M.p.  206°,  [a]D— 21°. 
Dissolves  in  0-5  part  of  water  and  in  4-5  parts  of  90  % 
alcohol ;  very  slightly  soluble  in  chloroform.  The  aqueous 
solution  is  neutral  in  reaction,  and  should  afford  no  precipi- 
tate with  platinic  chloride  solution  (absence  of  foreign 
alkaloids).  Hyoscyamine  sulphate  should  give  no  colour 
with  concentrated  sulphuric  acid. 

Atropine  Sulphate  (C17H23O3N)2'H2SO4.  676.— The 
crude  alkaloid,  together  with  that  regenerated  from  the 
mother  liquors  after  the  removal  of  /-hyoscyamine  oxalate, 
is  racemised  by  dissolving  52  parts  in  520  volumes  of 
95  %  alcohol  containing  4*16  parts  of  sodium  hydroxide 
(loc.  cit.).  The  solution  is  allowed  to  stand,  at  room  temper- 
ature, until  it  shows  no  optical  activity,  after  which  it 


70        ORGANIC  MEDICINAL  CHEMICALS 

is  neutralised  with  oxalic  acid,  the  alcohol  is  removed,  and 
the  oxalate  recrystallised  from  water  until  a  melting  point 
of  196°-!  97°  is  obtained.  From  this  the  base  is  regenerated 
and  converted  into  the  sulphate,  as  described  above  in  the 
case  of  hyoscyamine. 

Atropine  sulphate  is  a  white  crystalline  powder.  M.p. 
194°.  It  dissolves  in  0*4  part  of  water,  and  in  4  parts  of 
90  %  alcohol.  The  aqueous  solution  is  neutral  in  reaction, 
and  should  be  optically  inactive. 

No  colour  should  be  imparted  by  the  salt  to  sulphuric 
acid. 

Three  cubic  centimetres  of  a  i  in  60  solution  should  yield 
no  precipitate  when  mixed  with  i  c.c.  of  ammonia  solution 

(10  %). 

Atropine  C17H23O3N,  289,  is  prepared  by  regenerating 
the  base  from  the  pure  oxalate  and  crystallising  from 
aqueous  alcohol. 

Atropine  crystallises  in  colourless  acicular  crystals. 
M.p.  115*5°.  It  dissolves  in  450  parts  of  water  at  25°  and 
in  87  parts  at  80° ;  in  3  parts  of  90  %  alcohol  and  in 
i  part  of  chloroform.  It  should  be  optically  inactive  and 
no  colour  should  be  developed  on  treatment  with  sulphuric 
acid. 

Atropine  and  /-hyoscyamine  are  employed  chiefly  to 
dilate  the  pupil  of  the  eye  and  paralyse  the  accommodation. 
The  former  effect  is  due  to  paralysis  of  the  motor  nerve 
terminations  in  the  circular  muscle  of  the  iris  ;  the  latter  by 
the  action  of  the  alkaloid  on  the  nerve  endings  in  the  ciliary 
muscle.  The  two  alkaloids  have  qualitatively  the  same 
action,  but  pure  /-hyoscyamine  has  about  fifty  times  the 
mydriatic  power  of  atropine. 

Atropine  is  frequently  administered  hypodermically 
with  morphine,  to  counteract  the  undesirable  effects  of  the 
latter.  It  is  given  hypodermically  also,  to  diminish  the 
sweating  of  phthisis,  in  spasmodic  asthma,  narcotic  poison- 
ing, etc. 

Hyoscyamine  is  generally  used  in  the  form  of  its  hydro- 
bromide  or  sulphate. 


NATURALLY  OCCURRING  ALKALOIDS 


HYOSCINE  OR  SCOPOLAMINE  C17H21O4N.     303. 

-CH2       CHpOH 

N-CH3  CH- 


CH-CH-CH2 

L-o- 


>CH-CO-OCH-CH  —  CH2 

/  I  I 

NCHCH 


or 


King. 


32 

I 
CH-CH  ---  CH 


Hess. 


Naturally  occurring  hyoscine  is  a  combination  of  Isevo- 
tropic  acid  with  inactive  oscine.  It  is  found,  mostly  in 
conjunction  with  hyoscyamine,  in  many  species  of  Datum. 
In  D.  arborea,  D.  Jastuosa,  and  D.  metel,  the  alkaloid  consists 
chiefly  of  hyoscine  ;  whilst  D.  stramonium  contains  princi- 
pally hyoscyamine,  with  some  hyoscine.  It  is  present  also 
in  Scopolia  and  Hyoscyamus  species,  for  instance  in  Scopolia 
japonica  and  Hyoscyamus  niger. 

Datura  metel  is  probably  the  most  readily  available 
source  of  hyoscine.  The  powdered  drug  is  extracted 
with  hot  alcohol  and  the  crude  alkaloids  are  isolated  in 
the  same  way  as  has  been  described  under  hyoscyamine, 
except  that  sodium  bicarbonate  is  employed,  instead 
of  ammonia,  for  liberating  the  bases.  The  alkaloid  is 
neutralised  exactly  with  hydrobromic  acid  and  the  solution 
of  the  hydrobromide  concentrated.  The  salt  which 
crystallises  out  on  cooling  is  separated  and  purified 
by  recrystallisation  from  water,  until  of  constant  melting 
point. 

Hyoscine  Hydrobromide  C17H2iO4NHBr— 3H2O.  438. 
— Colourless  transparent  crystals,  which  dissolve  in  4  parts 
of  water  and  in  14  parts  of  90  %  alcohol.  Hyoscine  hydro- 
biomide  loses  12*3  %  of  moisture  at  100°. 

The  pure  laevo-  hydrobromide  melts,  when  anhydrous, 
at  193°  and  has  a  specific  rotation  of  [a]D — 227°  (for  the 
hydrated  salt).  The  commercial  product  is  often  mixed 
with  inactive  hyoscine  (m.p.  181°)  and  has  a  lower  melting 
point  and  rotation. 


72  ORGANIC  MEDICINAL  CHEMICALS 

The  aqueous  solution  should  be  neutral  in  reaction  to 
litmus,  but  is  frequently  slightly  acid. 

The  salt  should  afford  only  a  faint  yellow  colour  with 
sulphuric  acid.  Hyoscine  is  a  valuable  hypnotic  and 
sedative,  employed  in  treatment  of  all  forms  of  violent 
mania  and  cerebral  excitement.  In  conjunction  with 
morphine  it  is  administered  hypodermically  as  an  anaesthetic 
prior  to  an  operation.  Very  little  chloroform  is  required. 
This  treatment  is  becoming  extensively  employed  in  child- 
birth, and  is  known  as  "  Twilight  Sleep." 

Hyoscine  also  produces  mydriasis  and  paralysis  of 
accommodation ;  the  effect  is  obtained  more  quickly  than 
with  hyoscyamine  or  atr opine  but  is  not  so  lasting. 

HOMATROPINE  (Mandelyl  tropeine)  C16H21O3N.     275. 

CH2— CH- 

NCH3   CHOCOCH(OH)C6H5 

I  I 

CH2— CH CH2 

Homatr opine  is  prepared  by  condensing  together  mandelic 
acid  and  tropine.  Tr opine  is  obtained  by  boiling  crude 
atropine  or  hyoscyamine  sulphate  for  some  hours  with  an 
excess  of  dilute  sulphuric  or  hydrochloric  acid  or  of  baryta. 

The  solution  is  neutralised,  concentrated,  and  made 
alkaline  by  addition  of  caustic  soda,  and  the  base  is  then 
shaken  out  with  chloroform  and  purified  by  distillation 
under  diminished  pressure.  B.p.  141°  at  3-5  mm. 

Fig.  ii  illustrates  the  type  of  oil-jacketed  vacuum  still 
suited  for  this  operation;  the  twin  receiver  is  utilised  for 
separating  the  fractions.  The  condenser  water  must  be 
kept  at  65°  to  prevent  solidification  of  the  tropine. 

The  condensation  is  carried  out  as  follows  (see  D.  R.  P. 
95853,  also  Trans.  Chem.  Soc.,  95,  1020). 

One  molecular  equivalent  of  tropine,  14*2  parts,  is  mixed 

with  an  equivalent  of  mandelic  acid,  13-6  parts,  and  the 

mixture    heated    at   130°   in    a   stream   of    dry   hydrogen 

*  chloride,  for  7  hours.     The  product  is  treated  with  ammonia 

and  the  base  extracted  with  chloroform.     It  is  extracted 


NATURALLY  OCCURRING  ALKALOIDS        73 

from  this  solution  with  hydrobromic  acid,  and  the  neutral 
solution  of  the  hydrobromide  is  concentrated  and  allowed 
to  crystallise.  The  separated  crystals  are  purified  by  recry- 
stallisation  from  water  or  alcohol.  The  base,  regenerated 


FIG.  ii. — Vacuum  Still,  oil-jacketed. 

from    the    purified    hydrobromide    and    crystallised    from 
alcohol,  melts  at  96°. 

Homatropine  Hydrobromide  C16H2iO3NHBr.  356. 
—Small  colourless  rhombic  prisms.  M.p.  214°.  Soluble 
in  6  parts  of  water,  and  in  18  parts  of  90  %  alcohol. 


74 


ORGANIC  MEDICINAL   CHEMICALS 


The  solutions  are  neutral  to  litmus.  A  2  %  solution 
should  yield  no  precipitate  on  the  cautious  addition  of  5  % 
ammonia  solution.  Homatropine  does  not  give  the  Vitali 
reaction  :  0*1  gram  of  the  salt  is  added  to  5  drops  of  nitric 
acid  and  evaporated  to  dry  ness  in  a  porcelain  dish,  when  the 
residue  should  not  be  coloured  violet  upon  the  addition  of 
a  drop  of  alcoholic  potash  solution  (absence  of  atropine,  etc.). 

Homatropine  is  employed  as  a  mydriatic.  It  dilates 
the  pupil  more  rapidly  than  atropine,  and  the  effects  disap- 
pear in  about  a  quarter  of  the  time.  It  is  also  less  toxic 
than  atropine. 


THE  ALKALOIDS  OF  CINCHONA  BARK 

From  the  various  species  of  cinchona  bark  which  have 
been  investigated,  more  than  twenty  alkaloids  have  been 
isolated,  of  which  quinine,  quinidine,  cinchonidine,  and 
cinchonine  are  medicinally  the  most  important.  The  variety 
of  cinchona  official  in  the  British  Pharmacopoeia  is  Cinchona 
succirubra,  a  "  red  "  cinchona  bark,  which  is  cultivated  in 
Java  and  India.  For  the  manufacture  of  quinine  and 
associated  alkaloids,  however,  bark  from  the  species  C. 
ledgeriana  and  hybrids  of  this  with  C.  succirubra  are  mainly 
employed,  these  containing  higher  percentages  of  alkaloid, 
of  which  a  larger  proportion  is  quinine. 

From  figures  given  in  the  yearly  report  of  the  Dutch 
Government  Cinchona  Undertakings,  1904,  the  average 
quantities  of  quinine,  cinchonidine,  and  cinchonine  plus 
amorphous  alkaloids  contained  in  the  various  species  culti- 
vated in  Java  are  as  follows  : — 


Species. 

Quinine. 

Cinchonidine. 

Cinchonine  4-  amor- 
phous alkaloids. 

C.  ledgeriana 

per  cent. 
7 

per  cent. 
0'5 

per  cent. 
1-25 

Hybrid  of  C.  ledgeriana 

and  C.  succirubra 

5  '5 

°'5 

2-8 

C.  succirubra 

1-6 

i  '5 

3'4 

NATURALLY  OCCURRING  ALKALOIDS         75 

The  bulk  of  the  world's  quinine  supply  is  derived  from 
Java  cinchona,  though  an  important  quantity  is  now  manu- 
factured, under  Government  auspices,  in  India. 

QUININE  C2oH24O2N2.  324. — The  method  of  manufacture 
of  quinine  is  as  follows  : 

The  bark  is  sun  dried,  powdered,  and  ground  up  with 
30  %  of  its  weight  of  sifted  slaked  lime  and  90  %  of  a  5  % 
caustic  soda  solution.  The  mixture  is  extracted  in  steam- 


FIG.  12. — Steam-heated  ball  mill.    Manlove. 

heated  rotating  ball  mills  (Fig.  12),  or  some  other  type  of 
vessel  provided  with  powerful  stirrers,  with  hot,  high  boiling 
petroleum,  which  dissolves  out  the  alkaloids.  The  selection 
of  a  suitable  petroleum  oil  possessing  good  solvent  properties 
is  a  matter  of  importance.  After  several  hours  the  mechanism 
is  stopped  and  the  oil  solution  separated  as  completely  as 
possible  by  decantation.  It  is  replaced  by  a  further  quantity, 
three  extractions  being  made  in  all.  The  combined  extracts 
are  agitated  in  a  lead-coated  washer  (Fig.  13)  at  90°-ioo°, 


76 


ORGANIC  MEDICINAL  CHEMICALS 


with  a  0-45  %  aqueous  sulphuric  acid  solution,  sufficient 
in  quantity  to  form  the  neutral  sulphates.  The  oil  is  sepa- 
rated whilst  the  solution  is  hot,  and  is  used  for  extracting 
further  quantities  of  bark.  From  the  aqueous  solution, 
after  adjusting  the  acidity,  quinine  sulphate  crystallises  out 
on  cooling.  It  is  purified  by  being  recrystallised  from 
water,  using  animal  charcoal  as  a  decolouriser,  until  suffici- 
ently free  from  cinchonidine  and  cinchonine.  Quinine 
alkaloid  is  obtained  by  dissolving  the  sulphate  in  30-40 
volumes  of  water  containing  sulphuric  acid  and  allowing  the 
solution  to  flow,  with  stirring,  into  a  slight  excess  of  dilute 
sodium  carbonate  or  ammonia.  The  amorphous  precipitate 


FIG.  13. — Lead -coated  washer. 

is  filtered  off,  washed  until  free  from  sodium  or  ammonium 
salts,  and  dried,  first  in  a  centrifugal  machine,  and  subse- 
quently in  a  dark  drying  room  at  a  temperature  not  exceeding 

30°. 

Quinine  is  a  white  granular  powder  containing  about 
10  %  of  water.  When  anhydrous  it  melts  at  175°.  It  is 
sparingly  soluble  in  water  (i  in  1700  at  15°  and  i  in  900  at 
100°).  It  is  more  soluble  in  ammonia  solution  and  less 
soluble  in  fixed  alkali  solutions  than  in  water.  It  is  soluble 
(i  in  i)  in  ether.  The  anhydrous  base  dissolves  in  25  parts 
of  ether,  in  2  parts  of  chloroform,  and  in  200  parts  of 
benzene. 

Quinine  Sulphate  (C20H24O2N2)2H2SO4-f7jH2O.    881. 


NATURALLY  OCCURRING  ALKALOIDS         77 

— The  neutral  sulphate  is  the  most  extensively  used  salt  of 
quinine.  It  is  commonly  sold  in  the  form  of  light,  colourless, 
silky,  needle-shaped  crystals,  which  effloresce  in  dry  air  ;  but 
a  denser  form  is  occasionally  required  consisting  of  larger 
crystals.  Both  forms  readily  lose  part  of  their  water  of 
crystallisation  if  exposed  to  the  air. 

Quinine  sulphate  dissolves  in  800  parts  of  water  at  15°, 
in  25  parts  at  100° ;  in  6  parts  of  boiling,  and  in  100 
parts  of  cold,  90  %  alcohol.  It  is  required  to  comply  with 
the  following  tests  for  freedom  from  cinchonidine  and 
cinchonine. 

Ether  test :  Dissolve  4  grams  of  the  quinine  sulphate  in 
120  c.c.  of  boiling  water.  Cool  the  solution  slowly  to  50°, 
with  frequent  stirring.  Separate  by  nitration  the  purified 
quinine  sulphate  which  has  crystallised  out.  Evaporate 
the  filtrate  to  10  c.c.,  and  when  cool  add  5  c.c.  of  solution  of 
ammonia  (sp.gr.  0*959)  and  10  c.c.  of  pure  ether,  and  shake. 
Set  aside  in  a  cool  place  for  24  hours.  Collect  the  crystals, 
which  consist  of  cinchonidine  and  cinchonine  together  with 
some  quinine,  on  a  tared  filter,  wash  with  a  little  dry  ether, 
dry  at  100°  and  weigh.  The  weight  should  be  not  more 
than  O'i2  gram. 

Ammonia  test :  Two  grams  of  quinine  sulphate,  dried  at 
50°  for  2  hours,  are  mixed  with  20  c.c.  of  water,  kept  with 
occasional  agitation  at  6o°-65°  during  30  minutes,  then  cooled 
to  15°  and  kept  at  this  temperature  for  2  hours  with 
occasional  agitation.  It  is  then  filtered  and  5  c.c.  of  the 
filtrate  measured  into  a  dry  test  tube.  According  to  the 
United  States  Pharmacopoeia,  7  c.c.  of  ammonia  (0*958  at 
25°)  added  all  at  once  should  produce  a  clear  solution,  whilst 
the  German  Pharmacopoeia  stipulates  that  a  clear  solution 
should  be  produced  by  4  c.c.  of  ammonia  of  the  same  strength. 

The  other  most  generally  used  salts  of  quinine  are  : 

Quinine  bisulphate  C20H24O2N2H2SO4+7H2O.     548. 

Quinine  hydrochloride  C20H24O2N2HC1-|-2H2O.  396-4. 

Quinine  bihydrochloride  C20H24O2N22HC1-J-3H2O.  451. 

Quinine  hydrobromide  C20H24O2N2HBr+H2O.    423. 

Quinine  phosphate  (C20H24O2N2)2H3PO44-8H2O.  890. 


78  ORGANIC  MEDICINAL  CHEMICALS 

All  these  salts  are  readily  prepared  by  dissolving  quinine 
in  the  respective  acids,  and  may  be  crystallised  from 
water. 

Quinine  is  administered  most  frequently  as  a  prophylactic 
against  malaria  and  as  a  cure  for  this  disease,  against  which  it 
has  for  long  been  regarded  as  a  specific.  It  possesses  anti- 
pyretic properties,  apparently  by  direct  action  on  the  tissues, 
and  finds  much  application  in  general  medicine  on  this 
account.  In  small  doses  it  acts  as  a  bitter  stomachic  and 
tonic,  causing  increased  secretion  of  gastric  juice  in  the 
alimentary  canal,  with  consequent  improved  appetite  and 
digestion.  For  this  purpose  it  is  often  prescribed  in  the 
form  of  a  double  compound  with  iron — iron  and  quinine 
citrate. 

CINCHONIDINE  C19H22ON2.  294.— Cinchonidine,  together 
with  some  quinine,  cinchonine,  and  other  alkaloids, 
remains  in  the  liquors  from  which  quinine  sulphate  has 
crystallised.  The  alkaloids  are  precipitated  by  addition  of 
alkali,  dried,  and  extracted  repeatedly  with  small  quan- 
tities of  ether  or  chloroform,  by  which  treatment  cinchoni- 
dine,  quinidine,  and  quinine  are  dissolved  out,  leaving 
behind  the  more  sparingly  soluble  cinchonine.  The  solution 
is  agitated  with  hydrochloric  acid  and  the  alkaloids  con- 
verted into  their  neutral  hydrochlorides.  The  aqueous 
solution  of  these  is  treated  with  sodium  potassium  tartrate 
solution,  whereby  the  cinchonidine  is  precipitated,  mixed 
with  a  little  quinine,  as  tartrate.  This  is  separated,  treated 
with  aqueous  alkali,  and  the  base  filtered  off  and  dried  in 
vacuo  at  40°-45°  It  is  then  washed  with  absolute  ether 
until  it  no  longer  affords  a  green  colouration  when  treated 
with  chlorine  water  and  ammonia  solution  (thalleioquin 
reaction)  and  is  purified  finally  by  recrystallisation  from 
alcohol. 

Cinchonidine  forms  colourless  leaflets,  or  prisms.  M.p. 
206-5°.  It  dissolves  in  188  parts  of  ether  (sp.gr.  0720),  in 
16-3  parts  of  97  %  alcohol,  and  in  300  parts  of  50  %  alcohol. 
It  is  very  slightly  soluble  in  water  ;  dissolves  readily  in 
chloroform.  It  is  not  fluorescent  in  dilute  sulphuric  acid. 


NATURALLY  OCCURRING  ALKALOIDS         79 

The  salts  of  cinchonidine  most  commonly  employed  are 
cinchonidine  hydrobromide  (C19H22ON2-HBr+H2O),  393; 
cinchonidine  acid  hydrobromide  (Cl9H22ON22HBr+2H2O), 
492;  and  cinchonidine  sulphate  ((CigH^ONg^HaSC^HaO), 
740. 

Cinchonidine  is  used  as  a  substitute  for  quinine,  having  a 
similar,  though  weaker,  action. 

CINCHONINE  C19H22ON2.  294. — This  alkaloid  occurs  in 
most  species  of  cinchona. 

The  crude  cinchonine,  which  remains  undissolved  on 
treating  with  ether  or  chloroform  the  alkaloids  precipitated 
from  the  quinine  sulphate  mother  liquors  (see  Cinchonidine), 
is  recrystallised  from  alcohol,  adding  charcoal  to  decolourise 
the  solution. 

Cinchonine  forms  rhombic  prisms.  M.p.  264°,  [a]  0+229° 
in  dry  alcohol.  It  is  very  sparingly  soluble  in  water,  dis- 
solves in  370  parts  of  ether  (sp.gr.  0730),  in  280  parts  of 
chloroform,  in  126  parts  of  alcohol  (sp.gr.  0*852)  at  20°. 

Cinchonine  does  not  give  the  thalleioquin  reaction  and 
is  not  fluorescent  in  dilute  sulphuric  acid  solution.  The  fact 
that  it  is  very  sparingly  soluble  in  ether  and  forms  a  sparingly 
soluble  hydr iodide  distinguishes  it  from  quinine. 

Cinchonine  sulphate  (C19H22ON2)  2H2SO4 + 2H20, 722,  is 
employed  in  medicine  as  a  substitute  for  quinine,  to  which 
it  is  preferred  by  some,  but  it  is  much  weaker  in  its  action. 
The  dehydrated  salts  are  soluble  in  chloroform  (80  parts), 
(distinction  from  quinine  and  quinidine  sulphates). 

QUINIDINE  C20H24O2N2.  324. — Quinidine  is  isomeric 
with  quinine,  with  which  it  is  associated  in  various  species 
of  cinchona.  Quinidine  remains  dissolved  in  the  liquors 
from  which  cinchonidine  tartrate  has  been  precipitated 
(see  Cinchonidine)  and  is  precipitated  from  a  not  too  con- 
centrated solution,  as  the  sparingly  soluble  hydriodide, 
by  addition  of  potassium  iodide  solution.  The  precipitate 
is  treated  with  ammonia  solution,  the  base  dissolved  in 
acetic  acid,  and  the  solution  decolourised  by  treatment 
with  charcoal.  The  quinidine  is  reprecipitated  with  am- 
monia and  recrystallised  from  boiling  alcohol. 


8o  ORGANIC  MEDICINAL  CHEMICALS 

Anhydrous  quinidine  melts  at  171*5°  and  is  soluble  in 
35  parts  of  ether  and  in  26  parts  of  alcohol  (80  %)  at  20°. 
It  is  readily  soluble  in  chloroform,  sparingly  soluble  in  light 
petroleum  and  in  water. 

Quinidine  Sulphate  (C20H24O2N2)2H2SO4+2H2O.  782. 
— White  silky  crystals,  soluble  in  200  parts  of  cold  water. 

When  a  solution  of  0*5  gram  dissolved  in  10  c.c.  of  water 
at  60°  is  treated  with  0-5  gram  of  potassium  iodide,  cooled, 
kept  for  one  hour  and  filtered,  the  filtrate  should  afford  no 
precipitate  with  ammonia  solution  (absence  of  cinchonidine, 
cinchonine,  etc.). 

THE  ALKALOIDS  OF  STRYCHNOS  SPECIES 

STRYCHNINE  C21H22O2N2.  334.— Strychnine  and  Brucine 
are  found  in  various  species  of  Strychnos  indigenous  to 
the  East  Indies  and  India,  the  seeds  of  two  of  which  are 
employed  as  a  source  of  these  alkaloids,  i.e.  Strychnos 
Ignatii  and  Strychnos  Nux-Vomica.  The  former  contain 
2*0  to  2 '5  %  of  total  alkaloid,  two-thirds  of  which  is  said 
to  be  strychnine,  and  the  remainder  brucine  ;  in  the  latter 
species,  although  the  total  alkaloid  content  is  slightly  more 
(2*5  to  3*0  %),  somewhat  less  than  one-half  of  it  consists 
of  strychnine.  The  seeds  of  a  third  species,  S.  Tieute, 
found  in  Java,  contain  about  1*5  %  of  strychnine  with  only 
traces  of  brucine.  The  beans,  on  account  of  their  rough, 
horny  nature,  cannot  readily  be  powdered,  and  before  they 
can  be  subjected  to  extraction,  may  best  be  disintegrated  by 
one  of  the  following  methods : — 

(1)  By  steaming  under  pressure  in  a  boiler. 

(2)  By  passing  through  suitable  rolls,  after  being  softened 
by  a  preliminary  steeping  in  hot  water. 

(3)  By  powdering  in  a  ball  mill  after  gentle  roasting. 
The  first  method  is  the  one  generally  preferred.     The 

magma  thus  obtained  is  made  alkaline  by  treatment  with 
milk  of  lime  and  extracted,  in  a  vessel  provided  with  powerful 
beaters,  with  hot  solvent  naphtha.  The  solution  obtained 
is  extracted  whilst  hot  with  5  %  sulphuric  acid  sufficient  to 


NATURALLY  OCCURRING  ALKALOIDS          81 

form  the  neutral  sulphates.  On  cooling,  strychnine  sulphate, 
mixed  with  some  brucine  sulphate,  crystallises  out,  whilst 
most  of  the  brucine  sulphate,  which  is  more  soluble,  remains 
in  solution,  together  with  a  portion  of  the  strychnine. 

The  crude  crystalline  strychnine  sulphate  is  dissolved  in 
hot  water,  and  the  alkaloid  set  free  by  addition  of  sodium 
carbonate  solution  and  recrystallised  from  alcohol  until 
free  from  brucine. 

Alternatively,  the  total  alkaloid  may  be  precipitated  from 
the  solution  of  the  mixed  sulphates,  washed  with  successive 
portions  of  25  %  alcohol,  which  extracts  most  of  the  brucine, 
and  the  strychnine  finally  obtained  pure  by  crystallisation 
from  80  %  or  90  %  alcohol. 

Translucent,  colourless,  rhombic  prisms.     M.p.  265°. 

Very  slightly  soluble  in  water  or  ether  ;  dissolves  in  170 
parts  of  90  %  alcohol,  in  250  parts  of  70  %  alcohol,  and  in 
6  parts  of  chloroform. 

Strychnine  should  dissolve  in  concentrated  sulphuric 
acid  without  colour  formation  ;  it  should  not  be  coloured 
on  treatment  with  cold  concentrated  nitric  acid  (absence  of 
brucine) . 

The  more  important  salts  are  : — 

Strychnine  Hydrochloride  C21H22O2N2'HC1+2H2O. 
406*4.  Soluble  in  35  parts  of  water. 

Strychnine  Nitrate  C21H22O2N2-HNO3.  397.  Soluble  in 
63  parts  of  water. 

Strychnine  Sulphate  (C21H22O2N2)  2'H2SO4  +5H2O. 
856.  Dissolves  in  48  parts  of  water. 

Strychnine  is  used  in  medicine  chiefly  as  a  gastric,  cardiac, 
and  general  tonic.  In  medicinal  doses  it  slows  the  heart, 
raises  the  blood  pressure,  and  exerts  a  tonic  action  upon  the 
digestive  organs.  It  increases  peristalsis  and  is  a  frequent 
ingredient  of  medicine  for  the  cure  of  chronic  constipation. 
Strychnine  has  a  powerful  stimulant  action  on  the  central 
nervous  system  and  is  consequently  useful  in  the  treatment  of 
reflex  or  functional  paralysis. 

BRUCINE  C23H26O4N2.  394.— In  order  to  obtain  brucine 
the  alkaloids  remaining  in  the  mother  liquors  after  the 

i.  6 


82  ORGANIC  MEDICINAL   CHEMICALS 

separation  of  strychnine  are  converted  into  the  neutral 
oxalates.  These  are  dried,  and  extracted  at  a  low 
temperature  with  absolute  alcohol,  whereby  strychnine 
oxalate  is  dissolved  out.  The  residual  brucine  oxalate 
is  dissolved  in  hot  water,  and  after  decolourisation  with 
charcoal,  the  alkaloid  is  precipitated,  dried  and  extracted 
with  cold  acetone,  or  absolute  alcohol.  Strychnine  being 
very  sparingly  soluble,  much  of  it  is  thus  removed.  The 
brucine  is  finally  purified  by  being  recrystallised  from 
dilute  (25  %)  alcohol  until  free  from  strychnine.  Alter- 
natively, the  total  mixed  alkaloids  obtained  from  the  mother 
liquors  after  removal  of  the  strychnine  are  dried,  and  the 
brucine  is  extracted  by  treatment  with  cold  acetone,  and 
purified  as  above  by  recrystallisation  from  dilute  alcohol. 

From  this  solvent  brucine  crystallises  out  in  colourless 
transparent  monoclinic  crystals  containing  4  molecules  of 
water.  When  anhydrous  it  melts  at  178°.  Sparingly  soluble 
in  water,  readily  soluble  in  acetone  and  in  chloroform;  the 
hydrated  compound  dissolves  in  20  parts  of  90  %  alcohol. 

The  absence  of  strychnine  can  be  proved  by  warming 
the  alkaloid  at  90°  with  nitric  acid  (sp.gr.  1*05)  until  the  red 
colour  has  disappeared,  by  which  treatment  the  brucine  is 
destroyed.  On  making  the  solution  alkaline,  extracting 
it  with  a  mixture  of  chloroform  and  ether,  and  treating  the 
residue,  after  evaporation  of  the  solvent,  with  concentrated 
sulphuric  acid  and  a  trace  of  solid  potassium  bichromate, 
strychnine,  if  present,  is  revealed  by  the  formation  of  an 
intense  purple  violet  colouration,  passing  from  red  to  yellow. 

Brucine  is  little  used  in  medicine.  It  resembles  strychnine 
in  its  physiological  action  but  possesses  approximately  only 
one-eighth  the  toxicity  of  the  latter  alkaloid.  It  also  differs 
from  strychnine  in  having  a  more  powerful  curare-like  action. 

PILOCARPINE  CuH16O2N2.     208. 

C2H5—  CH—  CH—  CH2—  C  --  NCH3 


CO    CH2  CH— 

\/ 
Pilocarpine  is  a  constituent  of  the  leaves  of  Pilocarpus 


NATURALLY  OCCURRING  ALKALOIDS          83 

jaborandi,  and  Pilocarpus  microphyllus,  plants  indigenous 
to  South  America.  In  recent  years  the  so-called  jaborandi 
of  commerce  has  consisted  almost  entirely  of  the  latter 
variety.  The  quantities  of  crystalline  pilocarpine  nitrate 
yielded  by  samples  of  P.  jaborandi  and  P.  microphyllus 
examined  by  Paul  and  Cownley  (Pharm.  J.  1896,  IV.,  3,  i) 
were  0-67  %  and  0-45  %  respectively.  For  the  isolation  of 
the  alkaloid  powdered  jaborandi  leaves  are  exhausted  with 
hot  alcohol,  the  alcohol  is  distilled  off  and  the  residue  dis- 
solved in  ammoniacal  spirit,  the  solution  filtered  and  again 
freed  from  alcohol.  It  is  then  poured  while  hot  into  heated 
I  %  hydrochloric  acid  and  allowed  to  stand  during  a  few 
days  for  resin  to  separate.  The  pilocarpine  is  extracted  with 
chloroform  from  the  aqueous  extract,  after  rendering  alkaline 
with  ammonia.  The  chloroform  is  then  removed  by  distilla- 
tion and  the  residual  alkaloid  is  dissolved  in  a  small  quantity 
of  alcohol  and  the  solution  made  acid  with  nitric  acid.  A 
crystal  of  pilocarpine  nitrate  is  added  and  the  solution 
allowed  to  stand  until  crystallisation  is  complete.  The 
separated  crystals  are  filtered  off  and  purified  by  recrystalli- 
sation  from  alcohol. 

Pilocarpine  Nitrate  Ci1H16O2N2*HNO3,  271,  is  the  salt 
most  commonly  used  in  medicine.  It  forms  white  prismatic 
crystals.  M.p.  177°,  [a]D+8i°-83° ;  soluble  in  6-7  parts 
of  water  and  in  146  parts  of  alcohol  (95  %)  at  15°.  Addition 
of  ammonia  to  an  aqueous  solution  of  the  salt  should  not 
afford  a  precipitate. 

Pilocarpine  Hydrochloride  CUH16O2N2-HC1,  244-4, 
forms  white  powdery  crystals  from  alcohol.  It  is  very  soluble 
in  water  and  has  a  hygroscopic  tendency.  M.p.  203°-204°. 
Pilocarpine  is  a  powerful  diaphoretic  and  sialogogue.  It 
produces  persistent  sweating  and  salivation  and  is  prescribed 
in  the  dropsy  of  Bright's  disease,  in  uraemia,  and  to  remove 
pleural  and  peritoneal  effusion.  It  is  an  antidote  in  bella- 
donna poisoning,  and  is  a  common  constituent  of  lotions  and 
ointments  used  to  increase  the  growth  of  hair.  It  has  a 
depressant  action  on  the  heart  and  requires  to  be  used  with 
caution  in  cardiac  cases. 


84        ORGANIC  MEDICINAL   CHEMICALS 

SPARTEINE  C15H26N2.     234. 

CH  CH 

/I  \          /I  \ 

CH2  CH2  CH— CH2— CH  CH2  CH2 


I 
CH, 


CH2   CH2  CH2  CH2CH2CH2 


Sparteine  is  obtained  from  "  broom  tops,"  the  herbaceous 
branches  of  the  broom,  Cytisus  scoparius,  gathered  in  the 
spring  j  ust  before  flowering.  Broom  tops  yield  o  '23  to  o  *68  % 
of  sparteine,  according  to  the  time  of  collection,  being 
richest  in  March,  and  poorest  in  August,  after  flowering. 

For  the  extraction  of  the  alkaloid  the  ground  drug, 
without  previous  drying,  is  macerated  in  the  cold  for  3  or 

N 
4   days   with  —   dilute   sulphuric   acid.     The   extracts   are 

combined,  carefully  neutralised,  and  concentrated  to  a 
syrupy  consistency.  The  mixture  is  then  made  alkaline  and 
steam  distilled,  when  the  sparteine,  being  volatile,  passes 
over.  The  distillate  is  neutralised  to  methyl  orange,  or 
iodeosin,  with  sulphuric  acid  and  evaporated  to  dryness. 
The  sparteine  sulphate  so  obtained  is  crystallised,  first  from 
water,  then  from  alcohol  (50  %). 

Sparteine  sulphate  Ci5H26N2-H2SO45H2O.  422.— 
Colourless  prismatic  crystals.  When  anhydrous,  melts 
at  I36°-I38°.  Dissolves  in  0*5  part  of  water,  and  in  5 
parts  of  90  %  alcohol.  The  solutions  are  laevo-rotary,  having 
[a]D-22'I°. 

No  colour  should  be  yielded  with  sulphuric  or  nitric 
acid.  Sparteine  sulphate  is  a  cardiac  tonic  and  diuretic. 
It  slows  and  strengthens  the  pulse,  this  action  being  more 
rapid  but  less  persistent  than  that  of  digitalis. 

ESERINE  OR  PHYSOSTIGMINE  C15H21O2N3.  275.  — 
Eserine  occurs,  associated  with  eseramine  and  physovenine, 
in  the  seeds  (Calabar  beans  or  Ordeal  beans)  of  Physostigma 
venenosum,  Balfour,  a  plant  indigenous  to  West  Africa.  The 
ripe  seeds  contain  about  0*15  to  0^30  %  of  ether  soluble 
alkaloids. 


NATURALLY  OCCURRING  ALKALOIDS         85 

For  the  preparation  of  eserine  the  crushed  beans  are 
exhausted  with  hot  90  %  alcohol.  The  extract,  after  removal 
of  the  alcohol,  is  poured  while  hot,  with  violent  stirring,  into 
o'i  %  sulphuric  acid  ;  it  is  then  allowed  to  stand  until  cold 
and  filtered  from  fat,  etc.  To  the  clear  aqueous  solution 
is  added  a  slight  excess  of  sodium  bicarbonate,  and  the 
alkaloid  is  extracted  with  ether.  The  ether  is  concen- 
trated to  a  low  bulk  and  shaken  into  dilute  sulphuric  acid. 
The  acid  extract  is  separated  from  the  ether  and  the  aqueous 
liquid  carefully  neutralised.  An  excess  of  sodium  salicylate 
is  then  added  by  which  eserine  salicylate  is  precipitated. 
It  is  purified  by  repeated  crystallisations  from  alcohol. 

Eserine  Salicylate  C15H21O2N3-C7H6O3.  413.— The 
most  stable  and  convenient  salt  of  eserine  is  the  salicylate, 
which  is  made  as  described  above  or  by  neutralising  an 
ethereal  solution  of  the  alkaloid  with  a  solution  of  salicylic 
acid  in  the  same  solvent,  when  it  is  precipitated  as  a  crystalline 
powder.  The  crystallised  salt  is  dried  in  vacuo. 

Colourless  acicular  crystals.  M.p.  i86°-i87°.  Soluble 
in  130  parts  of  cold  water  and  in  15  parts  of  alcohol  (90  %). 

Eserine  Sulphate  (Ci5H21O2N3)2H2SO4.  648.— Physo- 
stigmine  sulphate  is  prepared  by  exactly  neutralising  the 
ethereal  solution  of  the  base  with  a  solution  of  sulphuric 
acid  in  absolute  alcohol  and  evaporating  the  liquid  in  vacuo  as 
quickly  as  possible. 

White,  deliquescent,  needle-shaped  crystals  (m.p. 
145°),  which  afford  a  neutral  aqueous  solution.  It  readily 
turns  pink  on  exposure  and  is  less  stable  than  the  salicylate 
or  hydrobromide. 

Eserine  Hydrobromide  C15H21O2N3-2HBr,  437,  forms 
white  needle-shaped  crystals  from  alcohol.  It  is  readily 
soluble  in  water  and  is  not  deliquescent.  M.p.  224°-226°. 

Salts  of  physostigmine  are  employed  to  contract  the 
pupil  of  the  eye,  in  ciliary  paralysis,  glaucoma,  etc.,  in 
painful  affections  of  the  eye,  and  to  break  down  adhesions 
due  to  iritis,  its  use  being  alternated  with  that  of  atropine. 
Physostigmine  is  also  used  as  an  antidote  in  cases  of  strych- 
nine poisoning. 


86  ORGANIC  MEDICINAL  CHEMICALS 

COLCHICINE  C22H25O6N.  399. — Colchicine  is  obtained 
from  the  seeds  and  corms  of  Colchicum  autumnale,  the 
autumn  crocus  or  meadow  saffron ;  it  also  occurs  in  other 
species  of  Colchicum  and  Merendera.  The  ripe  seeds  contain 
from  0-3  %  to  0*8  %  of  colchicine ;  the  corms  from  O'li  % 
to  0-4%. 

For  the  preparation,  the  seeds  are  extracted  with  hot 
90  %  alcohol.  The  extract  is  freed  from  spirit  and  diluted 
with  water,  filtered  from  fat,  and  shaken  out  repeatedly  with 
chloroform.  The  solvent  is  removed  by  distillation,  the 
residue  dissolved  in  water,  filtered,  and  the  colchicine  again 
shaken  out  with  chloroform.  The  chloroform  extract 
is  concentrated  until  it  is  nearly  viscous,  treated  with  a 
small  quantity  of  absolute  alcohol,  warmed  till  homogeneous 
and  kept  at  below  o°  until  crystallisation  is  complete.  The 
product  which  separates  consists  of  chloroform-colchicine 
C22H26O6N+2CHC13.  After  being  filtered  off  it  is  boiled 
with  water,  whereby  the  chloroform  is  split  off,  and  the 
aqueous  solution  of  colchicine  thus  obtained  is  evaporated 
to  dryness  in  vacuo.  The  mother  liquors  from  the  chloro- 
form-colchicine are  concentrated,  and  by  repetition  of  the 
above  treatment  a  further  quantity  is  obtained.  (Sec 
Monatshefte,  1883,  4,  162;  1886,  7,  557;  1888,  9,  i,  865.) 
An  alternative  method  is  based  on  the  power  of  tannic  acid 
to  precipitate  colchicine.  The  aqueous  solution  obtained 
by  dilution  of  the  alcoholic  extract  may  be  fractionally 
precipitated  with  this  reagent.  A  small  first  fraction  is 
rejected,  similarly  a  third  fraction.  The  second  and  main 
fraction  is  well  washed,  decomposed  by  treatment  with  lead 
oxide  and  the  colchicine  extracted  by  alcohol. 

A  yellowish  amorphous  powder,  soluble  in  chloroform, 
alcohol,  or  water,  slightly  soluble  in  ether.  M.p.  143°- 
147°.  Neutral  to  litmus. 

Colchicine  Salicylate  C22H25O6N-C7H6O3.  537-— 
Colchicine  is  used  in  medicine  mostly  in  the  form  of  its 
salicylate,  which  forms  a  faintly  yellow  crystalline  powder. 
It  is  used  as  a  remedy  for  gout,  in  which  it  relieves  the 
pain  and  inflammation.  The  galenical  extracts  of  the  seeds, 


NATURALLY   OCCURRING   ALKALOIDS       87 

however,  find  wider  employment  than  does  the  isolated 
alkaloid. 

ACONITINE  C34H47OHN.  645. — Aconitine  is  obtained 
from  the  root  of  Aconitum  Napellus,  a  plant  cultivated  in 
Britain,  France,  and  other  temperate  countries.  A  variety 
grown  in  Japan,  A.  uncinatum,  var.  japonicum,  affords 
japaconitine,  an  alkaloid  closely  allied  to,  but  not  identical 
with,  aconitine. 

European  aconite  root,  from  A.  Napellus,  contains  0*4  % 
to  0'6  %  of  alkaloids ;  other  varieties  contain  smaller 
quantities. 

For  the  isolation  of  aconitine  the  powdered  root  is 
extracted,  by  percolation  at  a  moderate  temperature,  with 
alcohol  acidified  with  tartaric  acid.  The  extract  is  freed 
from  alcohol,  which  is  removed  by  distillation  in  vacuo, 
and  treated  with  water  sufficient  in  amount  to  throw  out, 
in  a  filterable  form,  fat,  resin,  etc.  After  several  days' 
standing,  the  aqueous  portion  is  separated  by  filtration  and 
freed  from  last  traces  of  resin  by  agitation  with  petroleum 
ether.  The  alkaloid  is  then  precipitated  with  sodium 
carbonate  solution,  extracted  with  ether  and  purified  by 
conversion  into  its  hydrobromide,  which  is  recrystallised 
in  neutral  condition  from  water  until  of  constant  melting 
point.  The  alkaloid  may  be  obtained  by  precipitation 
with  ammonia  from  the  solution  of  the  pure  salt,  and  is 
crystallised  from  methyl  alcohol. 

Aconitine  crystallises  in  colourless  rhombic  crystals. 
M.p.  i97°-i_980.  It  is  soluble  in  726  parts  of  water, 
37  parts  of  absolute  alcohol,  40  parts  of  ether,  5-5  parts  of 
benzene,  and  is  almost  insoluble  in  petroleum  ether ;  it  is 
readily  soluble  in  chloroform. 

Aconitine  hydrobromide  C^H^OuN-HBi^^H^^ 
(from  water).  When  heating  is  commenced  at  160°,  it 
sinters  at  164°,  and  melts  at  180°. 

Aconitine  first  stimulates  and  then  depresses  the  respi- 
ratory centre,  and  in  toxic  doses  produces  death  by  respi- 
ratory failure.  It  is  antipyretic  and  slows  the  action  of 
the  heart. 


88  ORGANIC  MEDICINAL  CHEMICALS 

It  is  applied  externally,  embodied '  in  an  ointment,  to 
relieve  acute  nervous  pain,  such  as  that  of  acute  rheumatism 
and  gout  and  of  trigeminal  neuralgia.  Internally  it  relieves 
pain  and  high  temperature  and  is  useful  in  acute  local  inflam- 
mations, such  as  those  of  pneumonia,  peritonitis,  painful 
neuralgic  affections,  etc. 


SECTION  III.— NATURAL  AND  SYNTHETIC 
LOCAL  ANESTHETICS 

COCAINE  is  closely  allied  to  atropine  inasmuch  as  it  yields 
on  hydrolysis  ecgonine,  a  carboxylic  acid  derivative  of 
tropine,  the  hydrolytic  product  of  atropine, 

CH2— CH CH-COOH 

I     I 
NCH3  CH'OH 

I      I 
CH2— CH CH2         CH2— CH CH2 

Ecgonine.  Tropine.  • 

Cocaine  is  of  chief  importance  for  its  local  action  in 
paralysing  sensory  nerve  endings,  particularly  those  con- 
veying pain  and  touch. 

A  study  of  the  chemical  constitution  of  cocaine  has  been 
completely  successful  in  leading  chemists  to  produce  other 
substances  possessing  like  anaesthetic  action.  a-Bucaine 
was  the  first  substance  of  this  type  introduced,  but  was 
quickly  superseded  by  /3-eucaine,  which  is  less  toxic  than 
either  the  former  or  cocaine. 


CH3—  CCH3—  CH2  CH3'CCH3—  CH2 

CH3    COCH3  NH        CHOCOC6H5 


N 


CH3—  CCH3—  CH2  CH3-CH  -  CH2 

a-Eucaine.  /3-Eucaine. 

These  discoveries  led  to  others,  for  instance  the  alkamine 
esters  stovaine  and  alypine.     A  certain  chemical  resemblance 

89 


9o 


ORGANIC  MEDICINAL   CHEMICALS 


of  these  alkamme  esters  to  cocaine  is  shown  by  their  constitu- 
tional formulae : 


CH3  CH3 

I  I 

N— CH3    CH2 

CH2-    -COCOC6H6 
CH3 

Stovaine. 


CH3  CH3 
N— CH3  CH2 
CH2- C-OCOC6H5 


CH3N— CH2 
CH, 


Alypine. 


A  new  series  of  local  anaesthetics,  derivatives  of  amino 
benzoic  acid,  has,  however,  been  introduced,  and  these  do 
not  bear  any  marked  chemical  resemblance  to  cocaine. 
Some  of  these  compounds  have  attained  considerable  im- 
portance ;  the  simplest  of  them  is  ethyl  para-aminobenzoate, 
anaesthesine,  but  of  greater  importance  is  its  diethylamino 
derivative  known  as  novocaine. 

New  orthoform,  the  methyl  ester  of  aminohydroxy 
benzoic  acid,  is  another  useful  anaesthetic  of  this  class,  and 
an  improvement  on  this  is  the  diethyl  glycocoll  derivative 
of  ^-amino-methyl  salicylate  known  as  nirvanine. 

The  respective  merits  of  these  local  anaesthetics  are  to  be 
judged  not  merely  by  their  anaesthetic  action,  but  partly 
by  their  solubility  and  stability  during  sterilisation  by 
boiling,  and  especially  by  the  general  toxicity  and  local 
irritant  action.  The  following  interesting  table  of  comparison 
is  taken  from  Cushny's  Text-book  of  Pharmacology. 


Toxicity. 

Anaesthetic  action. 

Irritant  action. 

Cocaine    .      .      . 

I 

I 

+ 

Eucaine  . 

0-4 

I 

+  + 

Stovaine 

0-6 

I 

4-  + 

Alypine   . 

0-9—  1-25 

I 

+  +  +  + 

Novocaine    .      . 

0-3-0-5 

o-i 

Absent 

Nirvanine 

0-3-0-7 

0-4 

+  + 

NATURAL  AND  SYNTHETIC  ANAESTHETICS    91 

COCAINE  (Benzoyl  methyl  ecgonine)Ci7H2i  O4N.     303. 
CH2— CH CHCOOCH3 

N'CH3    CHOCOC6H6 

CH2 — CH CH.2 

Cocaine  is  obtained  from  the  leaves  of  various  species  of 
Erythroxylon.  Three  kinds  of  coca  leaves  occur  in  com- 
merce :  (i)  Erythroxylon  Coca,  Lamarck,  Huanuco  or  Bolivian 
Coca  ;  (2)  E.  Truxillense,  Rusby,  Truxillo  or  Peruvian  Coca, 
also  cultivated  in  Ceylon ;  (3)  E.  Spruceanum,  Burck,  Java 
Coca.  In  addition  to  the  foregoing  species,  many  varieties 
of  Erythroxylon  exist,  a  few  of  them  only  containing  signifi- 
cant proportions  of  cocaine.  The  percentage  of  alkaloids 
present  in  commercial  coca  leaves  varies  from  0'6  to  2*4, 
Java  leaves  containing  the  highest  amount.  Associated 
with  cocaine  are  a  number  of  other  alkaloids  :  cinnamyl- 
cocaine,  the  chief  constituent  of  the  Java  leaves ;  a-  and  j3- 
truxilline,  cocamine  or  isatropyl-cocaine,  and  benzoyl-ecgonine, 
which  possess,  with  cocaine,  the  common  property  of  affording 
ecgonine  on  hydrolysis,  together  with  benzoic,  cinnamic, 
or  truxillic  acids.  Tropacocaine,  another  important  consti- 
tuent, when  hydrolysed,  gives  pseudo-tropine,  a  stereo- 
isomeride  of  tropine,  and  benzoic  acid.  Ecgonine  can  be 
converted  into  cocaine,  by  methods  to  be  described  ;  pseudo- 
tropine  cannot. 

Crude  Cocaine. — In  order  to  save  freight  and  to  eliminate 
the  risk  of  deterioration  to  which  the  leaves  are  subject,  the 
alkaloids  are  commonly,  though  not  always,  extracted  in 
the  country  of  origin,  and  imported  into  Europe  under  the 
name  of  "  crude  "  cocaine,  which  may  consist  either  of  the 
bases  themselves,  or  of  their  hydrochlorides.  "  Crude " 
cocaine,  from  South  America,  is  an  extremely  variable 
article  and  frequently  is  heavily  adulterated.  Purchase  on 
assay  even  is  attended  by  risk,  as  the  same  keg  may  contain 
material  of  greatly  varying  purity. 

The  preparation  of  crude  cocaine  is  believed  to  be  carried 
out  in  South  America  by  extracting  the  finely  ground  leaves 


92  ORGANIC  MEDICINAL   CHEMICALS 

with  dilute  sulphuric  acid.  The  acid  extract  is  made  alkaline 
with  sodium  carbonate  and  the  liberated  alkaloids  are  dis- 
solved in  petroleum.  From  this  they  are  re-extracted 
into  dilute  sulphuric  acid  and  reprecipitated  with  soda,  the 
precipitate  being  washed  with  water,  pressed,  and  dried. 
(C.  and  D.  1912,  80,  51.) 

Java  cocaine,  from  which  a  very  large  proportion  of  the 
world's  supply  of  pure  cocaine  is  now  obtained,  is  manu- 
factured as  follows  :  the  leaves  are  dried  in  a  well-ventilated 
but  cool  place  and,  after  powdering  in  a  disintegrator,  are 
mixed  with  from  3  to  5  %  of  slaked  lime  and  sufficient 
water  to  afford  a  stiff  paste.  The  mixture  is  placed  in  a 
jacketed  iron  vessel  provided  with  good  stirring  facilities 
and  is  extracted,  at  a  temperature  of  8o°-ioo°,  with  a 
petroleum  fraction  distilling  at  200°-25o° ;  or,  in  the  cold, 
with  benzene  or  solvent  naphtha. 

The  oil  solution  after  separation  is  agitated  with  dilute 
hydrochloric  acid,  sufficient  in  amount  to  extract  the  bases 
in  the  form  of  their  hydrochlorides.  The  aqueous  solution 
is  then  either  neutralised  and  evaporated  down,  the  salts 
being  crystallised  out,  or  is  treated  with  sodium  carbonate, 
whereby  the  crude  cocaine  alkaloids  are  precipitated. 

Pure  Cocaine. — Although  it  is  possible  to  purify  cocaine 
by  crystallisation  of  the  hydrochlorides  of  the  mixed 
alkaloids,  this  procedure  has  been  found  to  be  tedious  and 
uneconomic ;  the  proportions  of  the  associated  alkaloids  vary 
considerably,  and  Java  cocaine,  as  has  already  been  stated, 
consists  mainly  of  the  cinnamyl  derivative.  The  technical 
method  of  manufacture  consists  of  hydrolysing  the  alkaloids 
to  methyl  ecgonine,  or  to  ecgonine,  and  reconverting  the 
purified  methyl-ecgonine  or  ecgonine  into  cocaine  by  benzoyla- 
tion,  or  esterification  and  benzoylation  respectively.  Hydro- 
lysis to  methyl-ecgonine  may  be  effected  by  boiling  with 
hydrochloric  acid  in  methyl  alcohol  under  a  reflux  condenser. 
For  complete  hydrolysis  the  hydrochlorides  of  the  alkaloids 
are  dissolved  in  water,  the  solution  is  made  acid  with  hydro- 
chloric acid  to  the  extent  of  about  0*2  %  and  heated  for  one 
hour  in  an  enamelled  or  silver-lined  autoclave  to  150°, 


NATURAL  AND  SYNTHETIC  ANESTHETICS    93 

whereby  the  methyl  group,  as  well  as  the  benzoyl,  cinnamyl, 
truxillyl,  etc.,  radicles  are  split  off.  The  resulting  solution 
is  filtered,  after  cooling,  from  the  liberated  acids  and  evapo- 
rated to  dryness.  Ecgonine  hydrochloride  is  thus  obtained, 
associated  at  times  with  some  pseudotropine  hydrochloride. 
It  is  washed  with  alcohol  or  acetone  and  the  base  isolated 
by  treatment  with  sodium  carbonate  and  extraction,  after 
drying,  with  hot  alcohol.  It  is  purified  by  crystallisation 
from  the  same  solvent,  from  which  it  separates  in  colourless 
prisms,  containing  i  molecule  of  water,  and  melting  at 
198°,  or  by  crystallisation  of  its  barium  salt. 

Methylation. — The  pure  ecgonine  is  converted  into  its 
methyl  ester,  by  heating  with  methyl  alcohol  and  hydro- 
chloric or  sulphuric  acid,  or  by  employing  sodium  methyl  sul- 
phate, and  the  ester,  after  liberation  from  its  salt,  is  extracted 
with  chloroform  and  cleaned  by  distillation  in  a  high  vacuum. 
Benzoylation. — Distilled  methyl-ecgonine  dissolved  in 
benzene  is  mixed  with  a  small  excess  of  benzoyl  chloride, 
and  the  mixture  heated  at  its  boiling  point  under  a  reflux 
condenser.  The  cocaine  hydrochloride  obtained  on  cooling 
is  converted  to  base  and  is  purified  by  recrystallisation 
from  alcohol.  The  hydrochloride  is  then  re-formed  and 
recrystallised  from  mixtures  of  alcohol  and  light  petroleum 
or  ether.  Recrystallisation  must  be  repeated,  if  necessary, 
until  the  pharmacopoeial  tests  of  purity  are  complied  with, 
since  associated  impurities  are  apt  to  possess  dangerous 
toxic  properties. 

Several  other  methods  have  been  proposed  for  the 
conversion  of  ecgonine  into  cocaine  : — 

Ecgonine  is  benzoylated  by  heating  with  benzoic 
anhydride  or  benzoyl  chloride,  or  by  heating  the  hydrochloride 
with  benzoyl  chloride,  and  the  resulting  benzoyl  ecgonine 
esterified  by  boiling  with  methyl  iodide  and  one  molecular 
proportion  of  sodium  in  methyl  alcohol  solution.  (I^ieber- 
mann  and  Giesel,  Ber.  1888,  21,  3196),  (D.  R.  P.  46702.) 

The  conversion  is  carried  out  in  one  operation,  whereby 
ecgonine  is  heated  together  with  methyl  iodide  and  benzoic 
anhydride  under  pressure.     (Merck,  Ber.  1885,  18,  2953.) 
The  hydrolysis  of  crude  cocaine  to  ecgonine  has  been 


94 


ORGANIC  MEDICINAL  CHEMICALS 


carried  out  by  boiling  with  an  excess  of  hydrochloric  acid 
(sp.gr.  1-1-1-2)  (D.  R.  P.  46702),  and  by  boiling  for  an  hour 
with  60  times  its  weight  of  7  %  hydrochloric  acid  (Greshoff, 
Pharm.  Weckbl.  1907,  44,  961).  De  Jong,  criticising  the 
latter  procedure,  has  stated  that  under  these  conditions 
decomposition  results.  (Chem.  Weckbl.  1907,  5,  645.) 

Tests  :  A  solution  of  0*1  gram  in  5  c.c.  of  water,  acidified 


FIG.  14, — Vacuum  Still  for  Methyl-ecgonine. 

with  3  drops  of  dilute  sulphuric  acid  (10  %  w/w)  is  mixed 
with  3  drops  of  decinormal  potassium  permanganate  solution, 
when  the  colour  should  not  disappear  in  half  an  hour 
(U.  S.  P.).  For  this  test  to  be  complied  with  it  is  necessary 
that  every  trace  of  organic  solvent  should  have  been  removed. 
A  solution  of  o-i  gram  of  cocaine  hydrochloride  in  80  c.c. 
of  water  is  treated  carefully,  without  shaking,  with  2  c.c.  of 
a  mixture  of  9  volumes  of  water  and  i  volume  of  10  % 


NATURAL  AND  SYNTHETIC  ANESTHETICS    95 

ammonia  solution  ;  no  turbidity  should  form  within  one 
hour.  On  then  scratching  the  sides  of  the  vessel  with  a 
glass  rod  a  crystalline  precipitate  (cocaine)  should  be  thrown 
down,  the  supernatant  liquor  remaining  clear. 

Cocaine  hydrochloride  should  melt  at  i8o°-i86°  (B.  P.), 
183°  (P.  G.),  186°  (Fr.  Codex).  It  should  be  perfectly  colour- 
less, and  should  afford  a  bright,  neutral  solution  in  water. 

This  salt  of  cocaine  is  the  one  most  generally  employed 
in  medicine.  It  is  largely  used  for  producing  local  anaesthesia 
in  minor  operations  and  in  dental  practice.  Given  internally, 
or  in  small  hypodermic  doses,  it  acts  as  a  nerve  stimulant, 
restorative,  and  tonic.  The  mental  exhilaration  it  produces 
often  conduces  to  the  formation  of  the  "  cocaine  habit," 
which  is  even  more  unfortunate  than  the  "  morphia  habit  " 
in  its  results. 

TROPACOCAINE    (Benzoyl   pseudotropine)    C15H19O2N. 

245. 

CH2— CH— CH2 

I         I 
NCH3  CHOCOC6H5 

I         I 
2— CH— CH2 

Tropacocaine  was  discovered  in  Java  coca  leaves  (Giesel, 
Ber.  1891,  24,  2336)  and  has  since  been  found  to  be  present 
in  Peruvian  coca  (Hesse,  J.  prakt.  Chem.  1902,  66,  401). 
Its  isolation  from  crude  cocaine  is  a  matter  of  difficulty  ; 
hence  it  is  technically  prepared  from  tropine.  Tropine  is 
boiled  with  sodium  amyloxide  in  amyl  alcohol,  prepared  by 
dissolving  sodium  in  dry  amyl  alcohol.  By  this  treatment  it 
is  converted,  to  a  large  extent,  into  its  stereoisomeride, 
T//-tropine  (Willstater,  Ber.  29,  936). 

The  base  thus  obtained  is  distilled  in  vacua  and 
crystallised  from  a  mixture  of  benzene  and  light  petroleum. 
About  65  %  of  pseudotropine  (m.p.  108°)  is  obtained, 
and  35  %  of  a  mixture  of  tropine  and  pseudo-tropine,  which 
is  mixed  with  the  next  batch  of  tropine  to  be  converted. 
It  is  benzoylated  in  the  same  way  as  has  been  described 
under  cocaine  (BarrowclifT  andTutin,  J.C.S.  1909,  95,  1970), 


96  ORGANIC  MEDICINAL  CHEMICALS 

and  the  resulting  tropacocaine  hydrochloride  purified  by 
recrystallisation  from  petroleum.  M.p.  271°  (Willstater)  ; 
283°  (Barrowcliff  and  Tutin). 

Tropacocaine  hydrochloride  forms  colourless  crystals 
readily  soluble  in  water.  It  should  withstand  permanganate 
to  the  same  extent  as  does  cocaine  hydrochloride,  when  the 
same  test  is  applied. 

Tropacocaine  is  employed  as  a  local  anaesthetic  and 
closely  resembles  cocaine  in  its  action.  It  is  said  to  possess 
only  one-half  the  toxicity  of  cocaine  and  to  produce  less 
dilation  of  the  pupil  of  the  eye.  Anaesthesia  sets  in  more 
rapidly  and  is  more  prolonged  than  in  the  case  of  cocaine. 

In  lumbar  anaesthesia  tropacocaine  is  indicated  as  the 
most  reliable  and  least  dangerous  of  the  drugs  in  use. 

BETA-EUCAINE  (Benzamine)  (Benzoylvinyl-diaceton- 
alkamine).  C16H2iO2N.  247. 

CH3 


C6H5CO—  0-^ 

CH3   CH3 

Beta-eucaine    is   prepared    according    to   the    following 
series  of  reactions 

2CH3COCH34-NH3  ->  CH3CO-CH2-C(CH3)2NH2 
116  17  115. 

Acetone.  Diacetonamine. 

+  CH3CH(OC2H6)2  -»    CH/C°XCH2 
118  |  | 

CH3-CHXNH/C(CH3)2 

141 

Acetal.  Vinyl-diacetonamine. 

^ 

CH.OCOC6H5  CHOH 


CH/XCH2  CHCH2 

I         I  S££22.  I          I 

CH3-CHv/C(CH3)2  CH3-CH^/C(CH3)2 

NH  NH 

247  143 

Benzoyl  vinyl-diacetonalkamine.  Vinyl-diacetonalkamine. 


NATURAL  AND  SYNTHETIC  ANAESTHETICS    97 

Diacetonamine  (see  Everest,  J.C.S.  115,  588  (1919)). 
— Acetone  (1160  parts)  and  anhydrous  calcium  chloride 
(200  parts)  are  introduced  into  a  water-cooled,  jacketed 
enamelled  vessel  provided  with  a  reflux  condenser  (to  prevent 
loss  of  acetone  during  the  introduction  of  ammonia),  a  stirrer, 
and  an  inlet  tube  leading  below  the  surface  of  the  liquid. 
Ammonia  gas  (from  a  cylinder)  is  passed  in  as  rapidly 
as  absorbed,  until  200  parts  have  been  added.  Heat  is 
developed  during  the  addition  of  the  ammonia,  and  care 
must  be  taken  that  no  loss  of  acetone  is  caused  thereby. 
The  addition  of  the  ammonia  occupies  about  nine  days, 
after  which  the  reaction  mixture  is  allowed  to  stand  for  a 
further  nine  days,  being  intermittently  stirred.  The  layers 
are  then  separated,  the  lower  one,  consisting  of  aqueous 
calcium  chloride,  being  removed.  Dry  air  is  then  passed 
rapidly  for  several  hours  through  the  a  mine  layer,  whereby 
a  large  proportion  of  the  excess  of  ammonia  is  removed. 
The  amount  of  oxalic  acid  required  for  the  formation  of  the 
acid  oxalate  is  determined  (by  titration  with  standard 
oxalic  acid)  ;  this  quantity  is  dissolved  in  alcohol  (S.V.M.), 
three  times  the  volume  of  the  reaction  mixture  being 
employed,  and  the  amine  then  poured  slowly  into  the  acid 
solution,  the  whole  being  well  agitated,  and  the  tempera- 
ture kept  below  50°.  The  mixture  is  then  distilled,  until 
the  temperature  reaches  75°,  when  a  small  amount  of 
acetone,  mixed  with  alcohol,  is  recovered.  The  solid 
ammonium  oxalate  which  separates  is  filtered  off  while  hot 
and  washed  with  hot  alcohol.  The  filtrates  deposit,  on 
cooling,  diacetonamine  acid  oxalate  in  a  crystalline  con- 
dition. It  is  collected,  washed  with  alcohol,  and  dried. 
From  the  total  mother  liquors  a  considerable  further 
quantity  of  product  is  obtained  by  distillation  at  water- 
bath  temperature,  allowing  the  residue  to  remain  for  about 
24  hours  in  the  cold,  collecting  the  crystals  which  separate,  and 
washing  them  with  alcohol.  About  800  parts  of  diaceton- 
amine acid  oxalate  are  obtained ;  600  parts  from  the  first 
deposition,  and  about  200  parts  from  the  liquors  and  by 
extraction  of  the  acid  residues.  M.p.  I25°-I27°. 

l-  7 


98  ORGANIC  MEDICINAL  CHEMICALS 

Vinyl-diacetonamine  Oxalate  (see  B.  P.  101738  of 
1916,  King,  Mason  and  Schryver). — Diacetonamine  acid 
oxalate,  800  parts,  is  mixed  with  alcohol  (S.V.M.),  2^00 
parts,  and  acetal,  1600  parts,  and  the  mixture  boiled  for  8 
hours  in  a  vessel  provided  with  a  reflux  condenser.  While 
still  warm,  the  crystalline  vinyl-diacetonamine  oxalate  is 
separated  by  filtration,  and  a  further  crop  is  obtained  after 
concentration  of  the  mother  liquor.  Yield,  85-90  %. 

The  product  is  purified,  and  separated  from  unchanged 
diacetonamine  acid  oxalate,  etc.,  by  washing  with  hot 
95  %  alcohol  until  a  dried  sample  melts  at  184°-! 85°. 

As  an  alternative  method  of  purification  600  parts  of 
crude  vinyl-diacetonamine  oxalate  are  dissolved  in  1500 
parts  of  boiling  water  ;  900  parts  of  caustic  soda  are  dissolved 
in  1000  parts  of  water  and  about  one-half  of  the  solution  is 
added  to  the  solution  of  the  vinyl  compound  and  the  precipi- 
tated sodium  oxalate,  if  any,  is  filtered  off.  The  vinyl- 
diacetonamine  base  is  precipitated  in  the  filtrate  by  the 
addition  of  the  remainder  of  the  sodium  hydrate  solution  and 
is  removed  by  extraction  with  a  solvent,  such  as  ether. 
The  solvent  is  distilled  off,  the  residual  base  amounting  to 
about  350-400  parts. 

Preparation  of  Vinyl-diacetone-alkamine. — The  following 
process  is  based  on  a  method  communicated  to  the  Royal 
Society  Committee  by  Professor  R.  Robinson  of  .Liverpool 
University. 

Vinyl-diacetonamine  oxalate,  280  grams,  or  an  equivalent 
quantity  of  the  base,  is  dissolved  in  boiling  amyl  alcohol, 
2000  grams,  and  175  grams  of  sliced  sodium  added,  in 
quantities  of  10  to  20  grams  at  a  time,  at  such  a  rate  that  the 
mixture  keeps  boiling.  This  operation  can  be  effected  in  a 
metal  vessel  provided  with  a  long  tube  as  a  reflux  condenser, 
and  a  side  tubulure  for  the  introduction  of  the  sodium. 
Shaking  must  be  vigorous  and  continuous  throughout. 
The  product  of  a  number  of  such  reactions  is  mixed  and  boiled 
in  a  vessel  provided  with  a  reflux  condenser,  until  the  base 
extracted  from  a  test-portion  has  the  correct  melting  point, 
I37°-I38°.  This  operation  may  take  from  30-40  hours. 


NATURAL  AND  SYNTHETIC  ANESTHETICS    99 

A  current  of  steam  is  then  blown  through  the  mixture, 
when  amyl  alcohol  and  the  alkamine  distil  over.  The 
layer  of  the  former  is  separated  and  washed  with  dilute 
hydrochloric  acid,  which  is  then  used  to  neutralise  the 
aqueous  portion  of  the  distillate.  The  solution  of  the 
vinyl-diacetone-alkamine  hydrochloride  is  evaporated  to 
dryness  and  purified  by  washing  with  acetone.  Yield, 
295  grams. 

The  base  obtained  by  dissolving  a  portion  of  the 
hydrochloride  in  water  and  precipitating  it  with  soda 
should  melt  at  I37°-I38°.  If  the  melting  point  is  incorrect 
the  material  requires  to  be  purified,  either  by  preparing 
the  free  base  and  recrystallising  it  from  benzene,  or 
by  recrystallisatidn  of  the  hydrochloride  from  alcohol  and 
water. 

Benzoylation  of  vinyl-diacetone-alkamine  hydrochloride. 
— A  mixture  of  equal  weights  of  benzoyl  chloride  and 
vinyl-diacetone-alkamine  hydrochloride  is  heated  at  130°- 
140°  (internal  temperature)  for  2  hours  and  then  at  160° 
until  evolution  of  fumes  of  hydrogen  chloride  is  no  longer 
noticeable.  The  pasty  mass  is  stirred  from  time  to  time.  The 
whole  operation  takes  about  3  hours.  After  cooling  some- 
what, the  solid  mass  is  digested  with  a  small  quantity  of 
hot  water  and  crushed.  When  cold  it  is  filtered,  and  washed 
with  successive  small  amounts  of  cold  water  until  the  colour 
has  been  removed.  It  is  then  dried  and  washed  with  ether 
or  benzene  to  remove  benzoic  acid.  The  beta-eucaine 
Irydrochloride  is  then  recrystallised  from  water  till  pure. 

Beta-eucaine  Hydrochloride  (Benzamine  Hydro- 
chloride)  C15H2iO2N-HCl,  283*4,  is  a  fine  white  crystalline 
powder.  The  melting  point  has  been  given  as  268°,  but 
Pickard  has  shown  that  the  pure  salt,  when  heated 
in  a  capillary  tube  sealed  at  both  ends,  melts  at  278°. 
It  is  soluble  in  12  parts  of  90  %  alcohol,  and  in  40 
parts  of  water ;  the  aqueous  solution  should  be  per- 
fectly bright  and  colourless.  It  should  also  dissolve  with- 
out change  of  colour  in  concentrated  sulphuric  and  nitric 
acids. 


ioo         ORGANIC  MEDICINAL  CHEMICALS 

Beta-eucaine  Lactate  (Benzamine  lactate) 
C16H2102N-C3H603.     337- 

For  the  preparation  of  this  salt  the  hydrochloride  is 
dissolved  in  hot  water  and  the  base  liberated  by  addition 
of  twice  the  theoretical  quantity  of  caustic  soda.  When 
cold  it  is  extracted  by  ether  and  the  ethereal  solution  dried 
with  anhydrous  potassium  carbonate.  Ivactic  acid  is  dis- 
solved in  ether,  to  a  40  %  solution,  and  dried  over  anhy- 
drous sodium  sulphate.  Slightly  less  than  the  theoretical 
quantity  (i  molecule)  of  this  is  added,  with  stirring,  to  the 
ethereal  solution  of  the  base.  After  two  hours'  standing 
the  lactate  has  completely  separated  and  is  filtered  off  and 
washed  with  dry  ether  and  dried. 

The  salt  is  a  white,  odourless,  crystalline  powder, 
soluble  in  4  parts  of  water  and  in  8  parts  of  alcohol,  giving 
clear  and  colourless  solutions.  The  lactate  is  more  usually 
employed  than  the  hydrochloride,  on  account  of  its  more 
ready  solubility  in  water. 

Beta-eucaine  is  a  powerful  local  anaesthetic,  similar  in 
action  to  cocaine  but  less  toxic,  somewhat  weaker,  and 
devoid  of  the  stimulating  properties  of  the  latter.  Further, 
it  neither  dilates  the  pupil  nor  contracts  the  blood  vessels 
as  does  cocaine.  Beta-eucaine  is  especially  useful  for 
ophthalmic  purposes.  It  is  usually  administered  in  a  2  % 
aqueous  solution.  Solutions  of  the  salts  can  be  sterilised 
by  boiling,  without  undergoing  decomposition. 

STOVAINE  (Benzoyl  dimethylaminodimethylethylcarbinol 
hydrochloride).  C14H2iO2N-HCl.  271-4. 

CH3 
C6H5-CO-0-C-C2H5 

CH2N(CH3)2'HC1 
Dimethylaminodimethylethylcarbinol 


C2H6 


NATURAL  AND  SYNTHETIC  'AN/ESTHETICS  "  101 

One  molecule  of  monochlor  ace  tone  (prepared  by  direct 
chlorination  of  acetone — D.  R.  P.  68039)  *s  treated,  in  absolute 
ether,  with  one  molecule  of  magnesium  ethyl  bromide.  The 
resulting  magnesium  compound  is  decomposed  with  ice 
and  the  monochlorodimethylethylcarbinol  extracted  and  dis- 
tilled (Tiffeneau,  Compt.  Rend.  134,  775).  This  is  next 
heated  with  2  molecular  proportions  of  30  %  dimethylamine 
solution  at  180°  for  3  hours.  The  solution  is  then  neutra- 
lised and  evaporated  to  dryness,  the  salt  treated  with 
concentrated  alkali,  and  the  dimethylaminodimethylethyl- 
carbinol  extracted  with  a  solvent  and  separated  from  re- 
covered dimethylamine  by  distillation  (D.  R.  P.  169746). 

By  another  method  (D.  R.  P.  169819)  dimethylamino- 
acetone,  prepared  from  monochloracetone  and  dimethyl- 
amine, is  treated  with  magnesium  ethyl  bromide  in 
anhydrous  ether  solution.  A  vigorous  reaction  ensues,  the 
ether  boils,  and  a  white  powder  separates.  The  addition 
of  the  dimethylaminoacetone  occupies  about  3  hours. 
The  reaction  mixture  is  allowed  to  stand  for  4-6  hours 
and  is  decomposed,  after  adding  powdered  ice,  with 
sufficient  nitric  acid  to  render  the  solution  acid.  The 
ether  layer  is  separated  and  the  acid  layer  concentrated  in 
vacuo  as  far  as  possible.  The  residue  is  treated  with  concen- 
trated alkali  solution  and  the  liberated  base  extracted  with 
ether  or  benzene,  and,  after  drying,  distilled  in  vacuo.  (B.p. 
57°  at  23  mm.,  140°  at  760  mm.) 

Benzoylation  of  Dimethylaminodimethylethykarbinol. — 
One  hundred  parts  of  the  distilled  base  are  mixed  with 
a  solution  of  115  parts  of  benzoyl  chloride  dissolved  in 
200  parts  of  benzol.  Heat  is  developed,  and  the  hydro- 
chloride  of  the  benzoylated  base  separates.  After  boiling  for 
some  time  the  reaction  mixture  is  cooled,  and  the  crystals  are 
filtered  off,  washed  with  cold  benzol  and  recrystallised  from 
absolute  alcohol,  or  by  dissolving  in  the  minimum  amount  of 
methyl  alcohol  and  mixing  with  an  equal  volume  of  acetone. 

Stovaine  is  sold  in  the  form  of  small  colourless,  glistening, 
scaly  crystals.  M.p.  175°.  It  is  very  soluble  in  water, 
and  the  solution  can  be  sterilised  by  boiling  without 


102         ORGANIC  MEDICINAL  CHEMICALS 

decomposition  taking  place.  It  is  readily  soluble  in  alcohol 
and  almost  insoluble  in  ether.  It  is  neutral  to  litmus. 

Stovaine  is  a  lumbar  anaesthetic  said  to  possess  only  one- 
half  the  toxicity  of  cocaine.  It  differs  physiologically  from 
cocaine  in  that  it  dilates  the  blood  vessels  instead  of  con- 
tracting them,  and,  further,  seems  to  have  a  tonic  effect  upon 
the  heart.  Hence  the  vascular  system  is  said  to  escape  all 
the  harmful  effects  produced  by  cocaine. 

ALYPINE  (Benzoyl  tetra-methyldiaminodimethylethyl- 
carbinol  hydrochloride)  Ci6H26O2N2-HCl.  314*4. 

CH2N(CH3)2-HC1. 

I 
C2H6-COCOC6H5 

I 
CH2N(CH3)2 

CH2C1 
Preparation   of   fi-EthyldicUorhydrin    C\^  5     D.R.P. 


CH2C1 

168941.  —  48  parts  of  magnesium  are  treated  with  a  mixture 
of  218  parts  of  ethyl  bromide  and  300  parts  of  abso- 
lute ether.  To  the  resulting  solution  of  magnesium  ethyl 
bromide  are  added,  slowly  and  with  careful  cooling  and 
good  stirring,  254  parts  of  symmetrical  dichloracetone, 
CH2C1—  CO—  CH2C1,  dissolved  in  an  equal  quantity  of 
absolute  ether.  The  mixture  is  allowed  to  stand  overnight 
and  is  then  poured  on  to  powdered  ice.  Dilute  sulphuric 
acid  is  added  in  quantity  sufficient  to  dissolve  the  precipi- 
tated magnesia,  after  which  the  ether  layer  is  separated, 
washed,  and  dried,  and  the  ethyldichlorhydrin,  after  removal 
of  the  solvent,  distilled  in  vacuo.  B.p.  77°  at  15  mm. 
Tetra-methyldiaminodimethylethylcarbinol 
CH2N(CH3)2 

C2H5—  C—  OH 

I 
CH2N(CH3)2 


NATURAL  AND  SYNTHETIC  ANESTHETICS    103 

D.  R.  P.  173610. — 157  parts  of  j8-ethyldichlorhy drin  are  treated 
with  a  solution  of  180  parts  of  dime  thy  lamine  in  water,  and 
the  mixture  is  heated  in  an  autoclave  for  3  hours  at  180°. 
The  resulting  solution  is  made  slightly  acid  with  hydrochloric 
acid  and  extracted  with  ether,  to  remove  unchanged  /?-ethyl- 
dichlorhydrin,  after  which  it  is  evaporated  to  dryness.  The 
residue  is  covered  with  a  layer  of  ether  and  is  treated  with 
concentrated  caustic  soda  solution  and  with  solid  caustic  soda 
to  saturation.  The  liberated  bases,  dimethylamine  and 
tetra-methyldiaminodimethylethylcarbinol,  are  taken  up  by 
the  ether.  The  ether  and  dimethylamine  are  removed  and 
the  residual  base  distilled  in  vacuo.  B.p.  87°  at  17  mm. 

Benzoyl  tetm-methyldiaminodimethylethylcarbinol  D.  P.  R. 
173631. — The  method  given  for  the  benzoylation  consists  in 
treating  147  parts  of  the  base,  mixed  with  crushed  ice,  with 
200  parts  of  20  %  caustic  soda  solution  and  140*5  parts 
of  benzoyl  chloride,  added  in  equivalent  amounts,  in  small 
quantities  at  a  time,  stirring  being  continuous  and  efficient. 
The  temperature  is  kept  at  o°  by  the  addition  of  ice. 
When  benzoylation  is  complete,  the  benzoylated  base  is 
extracted  with  a  solvent  and  converted  into  its  hydrochloride 
by  neutralising  with  an  alcoholic  solution  of  hydrochloric 
acid.  The  solution  is  evaporated  to  dryness  and  the  hydro- 
chloride  purified  by  recrystallisation  from  acetone. 

It  seems  probable  that  the  benzoylation  could  be  more 
simply  carried  out  by  treating  the  carbinol  derivative  with  a 
molecular  quantity  of  benzoyl  chloride,  as  in  the  case  of 
cocaine,  when  alypine  hydrochloride  should  directly  result. 

Alypine  hydrochloride  is  a  white  crystalline  hygroscopic 
powder,  melting  at  169°.  It  is  soluble  in  water  and  in 
alcohol.  The  aqueous  solution  is  neutral  in  reaction.  It 
should  be  protected  from  air. 

It  is  a  local  anaesthetic  having  an  action  similar  to  that  of 
cocaine,  than  which  it  is  stated  to  be  less  toxic.  It  is  also 
said  not  to  produce  disturbance  of  the  accommodation. 

NOVOCAINE  (^-aminobenzoyldiethylamino-ethanol  hydro- 
chloride)  NH2<^)>CO  -  O  -  CH2  -  CH2  -  N(C2H5)2HC1. 
272*4. — Novocaine  can  be  prepared,  according  to  D.  R.  P. 


104         ORGANIC  MEDICINAL  CHEMICALS 

179,629,  by  condensing  ^-nitrobenzoyl  chloride  with  ethylene 
chlorhydrin,  and  treating  the  resulting  ^-nitrobenzoyl- 
chlorethanol  with  diethylamine.  The  product,  ^>-nitro- 
benzoyldiethylamino-ethanol,  is  then  reduced  to  novocaine 
with  tin  and  hydrochloric  acid. 

By  D.  R.  P.  194748,  ^>-nitrobenzoylchlorethanol  is  first 
reduced  and  the  ^-aminobenzoylchlorethanol  condensed 
with  diethylamine  to  novocaine. 

The  researches  carried  out  under  the  direction  of  the 
Royal  Society's  Committee,  shortly  after  the  commencement 
of  the  war,  indicated  the  best  method  to  consist  in  first 
preparing  diethylamino-ethanol,  which  is  reacted  with 
^>-nitrobenzoyl  chloride,  the  resulting  compound  being  then 
reduced  to  novocaine. 

The  following  are  the  steps  by  which  diethylamino-ethanol 
is  prepared  : 


CH2Br    CH2OCOCH3 

CH2Br    CH2OCOCH3  CH2OH  ^  CH2-N(C2H5)2 

Ethylene                          Glycol  Glycol 

dibromide.                       diacetate.  bromhydrin.  71   OTT  OTT 

QQ  x    v^n2LAn 

T4°  I25  Diethylamino-ethanol. 


Dfethyl  aniline.  £-nitroso-diethyl  aniline.        Diethylamine. 

149  178  173 

Preparation  of  Glycol  bromhydrin.  —  Ethylene,  prepared 
either  by  the  usual  method  from  alcohol  and  syrupy 
phosphoric  acid,  or  by  passing  alcohol  vapour  through  a 
tube  containing  alumina  heated  at  320°-36o°,  is  passed 
into  bromine  and  the  resulting  ethylene  dibromide  purified 
by  fractional  distillation. 

Ethylene  dibromide,  188  parts  (i  mol.),  glycol  diacetate, 
146  parts  (i  mol.),  and  coarsely  powdered  potassium  acetate, 
206  parts  (rather  more  than  2  mols.),  are  well  mixed  together 
in  a  vessel  provided  with  a  reflux  condenser  and  a  powerful 
stirrer,  and  is  heated  in  an  oil  bath.  The  temperature  of  the 
bath  is  slowly  raised  to  about  150°,  when  ethylene  dibromide 


NATURAL  AND  SYNTHETIC  ANESTHETICS    105 

begins  to  boil  vigorously.  After  about  an  hour  very  little 
liquid  is  refluxing  and  the  temperature  is  raised  to  200° 
and  kept  at  this  point  for  i£  hours,  the  total  time  of  heating 
being  about  2^-3  hours,  stirring  being  continuous.  The 
reflux  is  then  replaced  by  a  direct  condenser,  to  which  a 
receiver  is  attached,  and  the  system  evacuated  to  10  mm. 
The  temperature  is  raised  finally  to  210°,  and  maintained 
at  this  until  no  more  liquid  distils  over.  The  distillate 
consists  of  glycol  diacetate,  acetic  acid,  and  ethylene 
dibromide.  It  is  redistilled  under  ordinary  pressure  and 
collected  in  three  portions:  (i)  i35°-i8o°,  (2)  i8o°-i9O°, 
(3)  above  190°. 

Fraction  (i)  is  refractionated  with  a  column,  distillation 
being  interrupted  when  the  thermometer  reaches  170°. 
The  distillate  (acetic  acid  and  ethylene  dibromide)  is  treated 
with  water  and  neutralised  with  potash,  ethylene  dibromide 
and  potassium  acetate  being  recovered.  The  residue  is 
mainly  glycol  diacetate,  used  in  the  next  stage*  of  the  reaction. 
Fraction  (3)  on  redistillation  affords  a  further  quantity  of 
glycol  diacetate.  Yield,  80-85  %  of  theory. 

The  glycol  diacetate  is  converted  into  glycol  bromacetate 
by  the  action  of  hydrogen  bromide,  according  to  the 
equation 

CH2OCOCH3       CH2Br 

|         -f  HBr  ->  |         +CH3COOH 

CH2OCOCH3       CH2OCOCH3 

Hydrogen  bromide,  81  parts,  prepared  from  bromine 
and  moist  red  phosphorus  and  dried  over  calcium  chloride, 
is  passed  into  146  parts  of  glycol  diacetate.  This  operation 
may  be  carried  out  in  a  closed  earthenware  still  suitable  for 
being  maintained  under  slight  pressure  of  the  gas.  If 
working  on  a  large  scale  a  stirrer  is  advantageous.  The 
brominated  liquor  is  allowed  to  remain  overnight,  after  which 
any  uncombined  hydrogen  bromide  is  removed,  by  blowing 
or  aspirating  a  current  of  air  through  the  liquid,  and  absorbed 
in  a  fresh  charge  of  glycol  diacetate.  The  liquor  is  then 
distilled,  to  remove  acetic  acid,  employing  a  fractionating 


io6         ORGANIC  MEDICINAL  CHEMICALS 

column  and  heating  up  to  125°.     The  distillate  is  refrac- 
tionated  once. 

The  glycol  bromacetate  without  further  purifying  is 
boiled  for  3  hours,  a  reflux  condenser  being  fitted,  with  70 
parts  by  volume  of  absolute  methyl  alcohol,  when  hydrolysis 
to  glycol  bromhydrin  and  methyl  acetate  occurs. 

CH2Br  CH2Br 

|  +CH3OH  ->  |  +CH3COOCH3 

CH2OCOCH3  CH2OH 

The  liquid  is  then  distilled,  using  a  column,  and  the 
methyl  acetate  and  excess  of  methyl  alcohol  are  removed. 
The  residue  is  distilled,  the  fraction  I46°-I5O°,  consisting  of 
glycol  bromhydrin,  is  reserved.  Anything  boiling  above  150° 
consists  chiefly  of  glycol  bromacetate  and  is  mixed  with 
the  next  batch  to  be  hydrolysed.  Yield,  76  %  of  theory 
(from  glycol  diacetate). 

An  alternative  method  for  the  preparation  of  glycol 
bromhydrin,  which  seems  to  possess  practical  possibilities, 
has  been  described  by  Read  and  Williams,  J.C.S.  Ill,  240 


Washed  ethylene  is  passed  into  an  ice-cold  solution  of 
7  '2  grams  of  bromine  in  500  c.c.  of  water.  After  complete 
absorption  of  the  bromine  a  fresh  portion,  equal  to  the  first, 
is  added,  with  frequent  and  vigorous  agitation,  until  a  total 
weight  of  200  grams  of  bromine  has  reacted.  The  lower 
layer  of  ethylene  dibromide  which  is  formed  during  the 
process  is  separated,  washed  with  water,  and  dried  over 
sodium  sulphate.  Yield,  88  grams.  After  neutralising  the 
sodium  carbonate  and  saturating  the  aqueous  layer  with 
common  salt;  the  ethylene  bromhydrin  is  extracted  from  it 
by  shaking  with  two  successive  quantities  of  100  c.c.  of  ether  ; 
from  the  extract,  dried  over  sodium  sulphate,  the  ether  is 
distilled.  The  bulk  of  the  residual  liquid  —  yield,  85  grams 
—  distils  between  145°  and  149°.  It  consists  of  glycol 
bromhydrin.  54-4  %  of  the  bromine  is  converted  into 
ethylene  bromhydrin  and  37-5  %  into  ethylene  dibromide. 
The  remainder  is  found  as  hydrobromic  acid,  which  should 
be  recoverable. 


NATURAL  AND  SYNTHETIC  ANAESTHETICS    107 

Preparation  of  Diethylamine.  —  From  diethylaniline  :  Di- 
ethylaniline,  50  parts,  dissolved  in  148  parts  of  hydrochloric 
acid  (sp.gr.  1-12)  diluted  with  75  parts  of  water,  is  diazotised 
with  a  solution  of  32  parts  of  sodium  nitrite  in  52  parts 
of  water,  the  temperature  being  kept  at  o°.  The  reaction 
mixture  is  allowed  to  stand  for  a  short  time,  then  run  slowly 
into  a  boiling  solution  of  85  parts  of  caustic  soda  in  2000 
parts  of  water,  contained  in  a  vessel  provided  with  a  con- 
denser and  receiver.  Diethylamine  is  distilled  off  and  is 
collected  in  an  excess  of  hydrochloric  acid.  The  boiling  is 
continued  for  45  minutes  after  all  the  nitroso  body  has  been 
added. 

The  solution  of  diethylamine  hydrochloride  is  then 
evaporated  to  dryness  and  the  dry  salt  gently  warmed  with 
strong  alkali  solution  (40  %  NaOH)  when  the  diethylamine 
which  is  liberated  is  distilled  over  and  obtained  pure  by 
one  further  rectification.  B.p.  55°-56°  ;  yield,  75  %  of 
theory. 

A  promising  alternative  method  for  the  preparation  of 
diethylamine  is  based  on  D.  R.  P.  105870. 

Toluene  para-sulphonamide  is  ethylated  by  heating 
with  two  molecules  of  caustic  soda  in  aqueous  solution  and 
two  molecules  of  ethyl  chloride,  in  an  autoclave  at  8o0-go0. 
Bthylation  takes  place,  a  diethyl  compound  being  formed. 

CH3<^])>S02NH2+2C2H5Cl+2NaOH 

~>    CH3<(^>SO2N(C2H6)2+2NaCl+2H20 

This,  on  heating  with  chlorsulphonic  acid,  is  decomposed 
into  toluene  sulphonchloride  and  diethylamine  sulphonic 
acid 


from  which  diethylamine  is  obtained  by  distillation  with 
alkali.  227  parts  of  toluene  parasulphondiethylamide  are 
mixed  with  130  parts  of  chlorsulphonic  acid  and  heated 


io8         ORGANIC  MEDICINAL  CHEMICALS 

for  2-3  hours  at  I30°-i5o°.  After  cooling,  toluene  sulphon- 
chloride  is  extracted  with  a  solvent  (petroleum,  benzene, 
or  ether),  the  residue  dissolved  in  water,  made  alkaline  with 
caustic  soda  liquor,  and  distilled,  whereupon  diethylamine 
passes  over  and  is  absorbed  in  hydrochloric  acid. 

Preparation  of  Diethylaminoethanol 

OH-CH2-CH2N(C2H5)2. 

— 438  parts  (2  mols.)  of  diethylamine  are  placed  in  a 
vessel  provided  with  a  stirrer,  an  efficient  reflux  condenser, 
and  a  tap  funnel,  through  which  375  parts  (i  mol.)  of  glycol 
bromhydrin  are  gradually  added,  the  rate  of  addition  being 
such  that  gentle  spontaneous  ebullition  takes  place.  Stirring 
is  continued  for  some  time  after  the  glycol  bromhydrin 
has  all  been  added,  and  the  reaction  mixture  is  allowed  to 
cool.  The  product  consists  of  the  hydrobromides  of  diethyl- 
amine and  diethylaminoethanol,  together  with  some 
diethylamine.  Concentrated  soda  liquor  (containing  140 
parts  of  NaOH)  is  added  and  the  mixture  stirred  until  all 
the  solid  has  passed  into  solution.  The  upper  layer,  consist- 
ing of  diethylamine  and  diethylaminoethanol,  is  separated 
and  dried  over  solid  caustic  soda.  The  lower  aqueous  layer 
is  extracted  twice  with  ether. 

The  mixture  of  bases  is  fractionally  distilled,  and 
separated  into  diethylamine  (b.p.  55°-58°)  and  diethyl- 
aminoethanol (b.p.  i58°-i63°).  The  residue  boiling  above 
163°  contains  a  little  diethylaminoethyl  acetate  and  is 
hydrolysed  by  boiling  with  methyl  alcohol  and  the  diethyl- 
aminoethanol separated  by  distillation.  Yield,  84  %  of 
theory. 

Pam-nitwbenzoyl  chloride  is  prepared  by  oxidising 
para-nitro-toluene  by  boiling  sodium  bichromate  and 
sulphuric  acid,  and  treating  the  resulting  para-nitro-benzoic 
acid  with  PC15.  The  product  is  fractionally  separated  by 
distillation  into  phosphorus  oxy chloride  and  para-nitro- 
benzoyl  chloride. 

Para-nitrobenzoyldiethylaminoethanol 

— OCH2—  CH2N(C2H6)2.    302-4. 


NATURAL  AND  SYNTHETIC  ANAESTHETICS    109 

117  parts  (i  mol.)  of  diethylaminoethanol  are  mixed  with  185*4 
parts  (i  mol.)  of  ^-nitro-benzoyl  chloride.  The  reaction,  which 
takes  place  spontaneously,  is  completed  by  heating  the 
mixture  for  2  hours  at  120°.  The  solid  product  consists  of 
the  hydrochloride  of  ^>-nitrobenzoyl  diethylaminoethanol. 

Para-aminobenzolydiethylaminoethanol  (novocaine  base) . 
236. — The  product  of  the  above  reaction  is  dissolved  in 
water  and  concentrated  hydrochloric  acid,  800  parts, 
and  treated  gradually  with  240  parts  of  granulated  tin, 
the  temperature  being  kept  at  35°-40°.  After  reduction  is 
completed  the  solution  is  freed  from  tin  with  H2S  and  filtered. 
It  is  made  alkaline  with  sodium  carbonate,  when  the  base 
separates  as  an  oil  which  presently  crystallises.  The  mass 
is  separated  and  recrystallised  from  dilute  alcohol,  from  which 
crystals  containing  2  molecules  of  water  and  melting  at  51° 
are  obtained. 

These  are  filtered  off  and  neutralised  with  one  molecule 
of  hydrochloric  acid.  The  salt  obtained  on  evaporation 
crystallises  from  alcohol  in  needles  melting  at  156°. 

Novocaine  is  a  white,  odourless,  crystalline  powder,  soluble 
in  an  equal  weight  of  water,  giving  a  neutral  solution.  It 
possesses  a  prompt  and  powerful  local  anaesthetic  action  when 
injected  subcutaneously.  It  is  non- toxic  and  has  no  irritant 
action  on  living  tissues.  It  is  particularly  useful  in  dental 
practice. 

AN.ESTHESINE,   ethyl  ^-amino-benzoate 

6-     165. 

— One  molecular  proportion  of  para-nitro-benzoic  acid,  pre- 
pared by  oxidising  pure  para-nitro-toluene,  is  dissolved  hi 
one  molecule  of  concentrated  aqueous  caustic  soda,  and 
the  solution  added  slowly  to  ij  mols.  of  crystallised 
sodium  sulphide  heated  at  100°.  The  mixture  is  then 
boiled  for  2  hours,  the  vapours  being  condensed  and  refluxed 
(cf.  D.  R.  P.  139568).  The  resulting  solution  is  poured  into 
3j  mols.  of  diluted  hydrochloric  acid,  and  the  SO2  expelled 
by  boiling.  After  filtering,  sodium  acetate,  i  J  mols.,  is  added. 
The  para-amino-benzoic  acid  crystallises  out  on  cooling. 
M.p.  i86°-i87°. 


no         ORGANIC  MEDICINAL  CHEMICALS 

It  is  esterified  in  the  usual  manner  by  heating  with 
alcohol  and  a  mineral  acid.  The  solution  is  neutralised, 
excess  of  alcohol  distilled  off,  water  added,  and  the  ethyl 
ester  filtered  off  and  recrystallised  from  alcohol. 

According  to  D.  R.  P.  147552,  10  parts  of  ethyl  ^-nitro 
benzoate  are  mixed  with  65  parts  of  40  %  sodium  bisulphite 
solution  and  200  parts  of  water,  and  heated  until  all  has 
passed  into  solution,  which  takes  place  in  from  f-i  hour. 
The  solution  is  evaporated  down,  or  salted  out,  when 
the  sodium  salt  of  ethyl  N-sulpho-^-aminobenzoate  is 

obtained  (COOC2H5/~\NHSO3Na).  This,  when  warmed 
with  concentrated  hydrochloric  acid,  gives  SO2  and  ethyl 
^-aminobenzoate. 

Ansesthesine  is  a  white  crystalline  powder.  M.p.  9O°-9i°. 
It  is  almost  insoluble  in  water,  soluble  in  alcohol  or  ether 
and  olive  oil.  Solutions  in  oil  may  be  sterilised  without 
decomposition. 

Anaesthesine  was  introduced  as  a  local  anaesthetic,  as  a- 
substitute  for  orthoform.  Unlike  that  of  cocaine,  its  action 
is  purely  local,  not  penetrating  the  mucous  membranes. 

It  is  employed  as  a  dusting  powder  or  in  an  ointment  for 
anaesthetising  wounded  surfaces,  such  as  burns,  and  for 
allaying  the  pain  of  ulcer ative  stomatitis,  also  in  tuberculosis 
and  malignant  ulceration  of  the  larynx  and  other  regions. 

NIRVANINE  (Diethylglycocoll  ^-aminomethyl  salicylate) 

_NH-CO'CH2N(C2H5)2 
COOCH3<(^)>  280. 

OH 

Several  methods  for  the  preparation  of  nirvanine  have  been 
protected,  of  which  the  best  would  seem  to  be  the  one 
covered  by  D.  R.  P.  108027,  in  which  methyl  ^-amino  salicy- 
late and  diethylglycocoll-ethyl  ester  are  condensed. 

JSTH2 
COOCH3<(_)>     +C2H5OCOCH2N(C2H5)  2 

167      OH  159 

_NHCOCH2N(C2H5)2 
->        COOCH3/_)>  +C2H5OH 

280      OH  46 


NATURAL  AND  SYNTHETIC  ANESTHETICS    in 

Methyl  p-amino  salicylate — For  the  preparation  of 
^-aminosalicylic  acid  (D.  R.  P.  96853)  30  kg.  of  meta- 
nitrobenzoic  acid  are  dissolved  in  250  kg.  of  sulphuric  acid 
(sp.gr.  1*84)  and  treated,  at  50°-8o°,  in  the  course  of  about 
4  hours,  with  45-50  kg.  of  zinc  dust.  After  standing  for 
10  hours  the  reaction  mixture  is  poured  on  to  ice,  and  the 
amido  salicylic  acid  sulphate  filtered  off  and  recrystallised 
from  hot  water.  M.p.  334°.  It  is  esterified  in  the  usual 
manner  by  boiling  with  methyl  alcohol  containing  sulphuric 
acid,  and  the  ester  isolated,  after  removal  of  excess  of  methyl 
alcohol,  by  adding  water  and  sodium  carbonate.  M.p.  96°. 

Diethylglycocoll  ester — Chloracetic  acid,  9-4  parts  (i  mol.), 
dissolved  in  water,  5  parts,  is  added  to  15  parts  of 
diethylamine,  with  stirring.  The  mixture  is  allowed  to  stand 
for  24  hours,  after  which  an  excess  of  HC1  is  added  and  the 
solution  evaporated  to  dryness.  A  mixture  of  diethylamine 
hydrochloride  and  diethylglycocoll  hydrochloride  is  obtained. 
It  is  treated  when  dry  with  40  volumes  of  absolute  alcohol 
and  HC1  gas  is  passed  in  to  the  point  of  saturation.  After 
standing  overnight  the  mixture  is  distilled  in  order  to  remove 
excess  of  alcohol,  and  the  residue  is  dissolved  in  water  and 
made  alkaline  with  sodium  carbonate  solution.  The  bases  are 
extracted  with  ether  and  the  solution  is  dried  over  anhydrous 
sodium  sulphate  and  fractionally  distilled.  Diethylamine 
is  first  recovered,  mixed  with  ether,  from  which  it  may  be 
extracted  with  a  further  quantity  of  chloracetic  acid  and 
the  diethyl  glycocoll  ethyl  ester  is  obtained  as  a  fraction 
boiling  at  177°. 

Condensation  of  diethylglycocoll  ester  and  p-amido  methyl 
salicylate  (D.  R.  P.  108027). — 5  parts  of  ^-amido  methyl 
salicylate  and  2*5  parts  of  diethylglycocoll  ester  are 
mixed  and  heated  together  for  several  hours  at  I5o°-i6o°, 
until  evolution  of  alcohol  can  no  longer  be  detected.  The 
reaction  product  is  then  dissolved  in  water,  and  made  alkaline 
with  sodium  carbonate.  The  solution  is  now  acidified  with 
acetic  acid,  the  nirvanine  base  extracted  with  ether  and  con- 
verted into  the  hydrochloride,  which  is  the  salt  commonly 
employed. 


H2         ORGANIC  MEDICINAL   CHEMICALS 

According  to  D.  R.  P.  106502,  methyl  ^-aminosalicy- 
late  is  condensed,  in  benzene  solution,  with  chloracetyl 
chloride,  and  the  resulting  methyl  />-chloracetylamino 
salicylate  converted  into  nirvanine  by  heating  with  diethyl- 
amine.  By  a  variation  of  this  method,  D.  R.  P.  108871, 
^>-aminosalicylic  acid  is  reacted  with  chloracetyl  chloride, 
and  the  product  treated  with  diethylamine,  when  diethylgly- 
cocoll  ^>-aminosalicylic  acid  is  produced  and  is  converted 
into  nirvanine  by  esterification  with  methyl  alcohol  and  HC1. 

Nirvanine  forms  small  white  prisms,  readily  soluble  in 
water.  M.p.  185°.  It  is  employed  as  a  local  anaesthetic 
in  surgical  and  dental  operations.  It  has  less  toxicity  than 
cocaine  and  about  half  its  anaesthetic  action. 


SECTION   IV.— ANTIPYRETICS    AND 
ANALGESICS. 

PRIOR  to  the  introduction  of  synthetic  remedies,  quinine  and 
aconitine  were  the  chief  active  drugs  employed  in  reducing 
high  temperature.  The  introduction  of  the  synthetic 
remedies  of  this  class,  which  are  now  so  well  known,  has  made 
it  possible  to  attain  this  therapeutic  object  without  the  ill 
effects  attendant  on  the  use  of  substances  as  toxic  as  aconitine. 

Salicin,  a  glucoside  of  salicylic  alcohol  occurring  in  the 
bark  of  the  willow,  has  also  been  employed  for  this  purpose, 
thus  leading  to  the  use  of  salicylic  acid,  the  first  of  the 
synthetic  coal  tar  derivatives  introduced  into  medicine. 
The  methyl  and  phenyl  esters  and  acetyl  derivative  of 
salicylic  acid  later  came  into  use  ;  the  last  mentioned,  under 
the  name  aspirin,  being  now  more  widely  employed  than 
any  other  drug  of  this  class. 

Antipyrine,  which  was  introduced  in  1884,  has  proved  of 
great  value  on  account  of  its  positive  action,  but  as  this  is 
frequently  accompanied  by  collapse,  other  and  safer  sub- 
stances of  the  type  of  phenacetin  have  found  wide  accept- 
ance. The  first  of  these  to  be  introduced  was  acetanilide. 
They  are  said  to  owe  their  activity  to  the  formation  of  simple 
derivatives  of  para-aminophenol  in  the  tissues.  If  this 
happens  rapidly  there  is  a  tendency  to  collapse  and  the 
antipyretic  action  is  too  quickly  over.  Consequently,  those 
members  of  this  class  which  decompose  gradually  in  the  blood, 
such  as  phenacetin  and  lactophenin,  are  preferred  to  acet- 
anilide and  exalgin,  which  are  regarded  as  dangerous. 
Phenacetin  is  the  para-ethoxyl  derivative  of  acetanilide  ;  the 
methyl,  propyl  and  butyl  members  of  the  series  have  been 
i.  IX3  8 


ii4         ORGANIC  MEDICINAL  CHEMICALS 

examined  pharmacologically  and  found  inferior  to  phenacetin. 
The  N-ethyl  derivative  of  phenacetin  is  said  to  be  superior 
to  phenacetin. 

The  drugs  of  this  class  remove  the  symptoms  of  disease 
rather  than  its  cause  and  their  use  as  curative  agents  has  been 
questioned. 

They  are  effective  in  reducing  pain,  and  because  of  value 
in  headache  and  in  relieving  rheumatic  and  neuralgia  pain, 
they  are  much  sought  by  the  public  apart  from  medical 
advice,  not  infrequently  with  untoward  effects. 

ACETANILIDE  (antifebrin)  C8H9ON.     135. 

C6H5NH-COCH3 

The  method  given  by  Muller,  Chem.  Zeit.  36  (1912),  1050, 
1055,  described  in  detail  by  Cain  in  The  Manufacture  of 
Intermediate  Products  for  Dyes,  page  51,  is  not  suitable 
for  manufacturing  acetanilide  of  pharmaceutical  quality, 
as  the  product,  on  account  of  the  high  temperature  attained 
(240°)  and  the  length  of  time  of  heating,  about  80  hours, 
is  highly  coloured  and  difficult  to  purify.  It  is  found  better 
to  mix  together  the  whole  of  the  ingredients,  500  Ib.  of 
aniline  and  500  Ib.  of  glacial  acetic  acid,  in  a  steam  jacketed 
enamelled  still  of  150  gallons  capacity,  and  to  heat  the 
mixture  at  a  temperature  of  I2O°-I25°,  the  heating  being 
so  regulated  that  practically  no  vapour  passes  over  into  the 
condenser.  The  progress  of  the  acetylation  is  followed, 
after  the  lapse  of  8-9  hours,  by  diazotising  a  portion  of  the 
reaction  mixture,  coupling  with  an  alkaline  solution  of 
£-naphthol  or  R-salt,  and  measuring  the  colour  intensity, 
which  indicates  the  quantity  of  aniline  unchanged.  When 
the  test  is  negative,  in  10-12  hours,  vacuum  is  applied  and 
as  much  acetic  acid  recovered  as  will  readily  distil  off  at 
120°. 

The  residue  is  then  blown  into  200  gallons  of  water  and 
allowed  to  cool.  The  crude  acetanilide  which  separates  is 
centrifuged,  the  filtrate  being  employed  to  receive  a  further 
batch  from  the  still.  The  acetanilide  is  recrystallised  from 
boiling  water,  of  which  about  1000  gallons  will  be  required, 


ANTIPYRETICS  AND  ANALGESICS         115 

using  a  good,  decolourising  charcoal.  From  the  filtered 
solution  pure  acetanilide  crystallises  out  on  cooling.  It 
is  separated  by  means  of  a  centrifuge,  washed  with  a  little 
water  and  dried  in  a  warm  room.  The  liquors  are  used  for 
the  recrystallisation  of  further  batches  of  crude  acetanilide. 

Acetanilide  forms  colourless,  glistening  plates,  m.p. 
Ii3°-ii4°.  It  dissolves  in  190  parts  of  cold,  in  18  parts  of 
boiling,  water  ;  in  12  parts  of  60  %  alcohol,  and  in  4  parts 
of  90  %  alcohol.  The  solutions  are  neutral  to  litmus. 

Colourless  solutions  should  be  afforded  in  concentrated 
sulphuric  and  nitric  acids,  and  a  sample  should  leave  no 
residue  on  ignition.  Acetanilide  is  a  powerful  antipyretic 
and  is  useful  for  treatment  of  the  high  temperatures  of  typhoid 
fever,  phthisis,  acute  rheumatism,  and  smallpox.  It  acts 
as  an  analgesic  in  neuralgia  and  other  nerve  affections. 

METHYLACETANILIDE  OR  EXALGIN  C9HUON.     149. 

C6H5NCH3COCH3 

Exalgin  may  be  prepared  according  to  the  method  given  in 
Ber.  io,  328.  Four  parts  of  acetanilide  are  added  to  25  parts 
of  anhydrous  xylene  containing  i  part  of  granulated  sodium. 
The  mixture  is  heated  at  130°,  with  continuous  stirring, 
for  2-3  hours.  The  sodium  salt  of  acetanilide  is  formed  and 
separates  in  the  form  of  a  white  gelatinous  mass.  After 
cooling,  a  slight  excess  of  methyl  iodide  is  -added  ;  reaction 
sets  in  spontaneously,  and  is  carried  to  completion  by  gentle 
heating.  The  mixture  of  methylacetanilide  and  sodium 
iodide  is  filtered  off,  washed  with  water,  which  removes  the 
latter  substance,  and  recrystallised  from  boiling  water.  In 
this  solvent  it  is  apt  to  form  supersaturated  solutions,  which 
require  seeding  with  a  crystal  to  induce  crystallisation. 

It  may  also  be  made  by  the  interaction  of  pure  mono- 
methyl  aniline  with  acetyl  chloride  or  acetic  anhydride. 

Bxalgin  crystallises  in  colourless  prismatic  needles. 
M.p.  101°.  It  is  soluble  in  50  parts  of  cold  water,  in  2 
parts  of  90  %  alcohol,  and  in  4  parts  of  60  %  alcohol. 

Exalgin  resembles  acetanilide  in  its  action  ;  it  is  employed 
as  an  analgesic,  in  neuralgia  and  toothache. 


Ii6         ORGANIC  MEDICINAL  CHEMICALS 
PHENACETIN  (acetphenetidine)  C10H13O2N.     179. 


Phenacetin  is  prepared  either  by  the  acetylation  of  para- 
phenetidine  C2H5OC6H4NH2,  or  by  ethylating  ^-acetamino- 
phenol  OHC6H4NHCOCH3. 

^-Phenetidine  can  be  prepared  either  by  the  reduction 
of  para-nitrophenetol,  produced  by  the  ethylation  of 
para-nitrophenol,  or  it  may  be  formed  by  the  reduction 
of  ^-diethoxyazobenzol  OC2H5<^^N  =  N<^^OC2H6. 
The  latter  process  will  be  given  first,  after  which  will  be 
described  various  technical  methods  for  preparing  para- 
nitrophenol,  and  for  its  conversion  into  />-nitrophenetol  and 
^-phenetidine  respectively. 

From  Phenetidine.  —  Preparation  of  p-p'-diethoxyazobenzol 
and  its  reduction  to  p-phenetidine.  —  The  process  consists, 
in  essence,  in  the  conversion  of  i  mol.  of  phenol  and 
I  mol.  of  phenetidine  into  2  mols.  of  phenetidine.  13*7 
kilos  of  para-phenetidine  are  dissolved  in  200  litres  of 
water  and  37-5  kilos  of  20  %  hydrochloric  acid.  The 
mixture  is  maintained  below  +6°,  and  diazotised  with  a 
solution  of  6  -3  kgs.  of  sodium  nitrite  dissolved  in  50  litres  of 
water.  The  diazo  solution  is  then  allowed  to  flow,  with 
stirring,  into  a  solution  of  9-5  kgs.  of  phenol  and  20  kgs.  of 
sodium  carbonate,  cryst.  in  350  litres  of  water.  In  the  course 
of  an  hour  ^>-ethoxy-^>-oxyazobenzol  separates,  in  quanti- 
tative yield.  M.p.  104*5°. 

C2H5OC6H4NH2  ->  C2H5OC6H4N=NCl-hC6H5OH 
137  184-4  94 

~>  C2H5OC6H4N=NC6H4OH 

242 

24*2  kilos  (i  mol.)  of  />-ethoxy-^>-oxyazobenzol  are 
dissolved  in  100  litres  of  alcohol  containing  4  kilos  (i  mol.) 
of  caustic  soda  and  heated,  in  a  lead-lined  autoclave,  at 
90°-ioo°,  for  5-6  hours,  with  7  kilos  (i^  mol.)  of  ethyl 
chloride.  After  cooling,  the  ^>-^>-diethoxyazobenzol  is 


ANTIPYRETICS  AND  ANALGESICS         117 

filtered,  the  filtrate  being  used  in  another  operation.     M.p. 
of  diethoxyazobenzol,  156°. 

C2H6OC6H4N  =N-C6H4OH  +C2H5C1  -f-NaOH 
242  64-4 

->  C2H5OC6H4N-NC6H4OC2H5+NaCl+H20 
270 

Ten  kilos  of  ^-^-diethoxyazobenzol  are  mixed  with  50  kgs. 
of  20  %  hydrochloric  acid  and  reduced  with  6  kilos  of 
granulated  tin.  When  all  has  dissolved,  the  reaction  liquor 
is  made  alkaline  with  caustic  soda  solution  and  the 
^>-phenetidine  distilled  over  by  means  of  superheated  steam 
(i6o°-i8o°).  (See  D.  R.  P.  48543.) 


C2H5OC6H4N=NC6H4OC2H5+2H2  - 

270  274 

Preparation  of  p-phenetidine  from  p-nitrophenol.  —  p-Nitro- 
phenol  OH<^^>NO2  is  now  prepared  technically  by  heating 
with  caustic  alkali  solution  or  lime,  para-chlornitro- 
benzene  Cl<^  yNO2,  which  is  a  product  of  the  nitra- 
tion of  chlorbenzol.  It  can  be  readily  obtained  pure  by 
distillation. 

Particulars  of  the  older  method,  by  which  phenol  is 
nitrated  directly,  are  given  by  Barnett  (Coal  Tar  Dyes  and 
Intermediates,  p.  25).  A  mixture  of  the  ortho-  and  para- 
isomerides  is  formed,  and  separated  by  distillation  in  super- 
heated steam,  ortho-nitrophenol  being  volatile,  para-nitro- 
phenol  non-  volatile. 

Para-nitrophenol  can  also  be  prepared  (D.  R.  P.  91314) 
by  condensing  phenol  with  par  a-  toluene  sulphonchloride 

to  CH3<(^>SO2OC6H5,  which,  on  nitration,  affords  the 
/>-nitrophenyl  ester  of  o-nitrotoluene-^-sulphonic  acid 
CH3<^^>SO2O<(^y>NO2.  This  compound,  on  heating  with 

NO2 

caustic  soda  solution,  is  resolved  into  para-nitrophenol  and 
ortho-nitrotoluene-p  ara-sulphonic  acid. 


u8         ORGANIC  MEDICINAL  CHEMICALS 

Ethylation  of  p-Nitrophenol. — 139  parts  (i  mol.)  of  para- 
nitrophenol  are  dissolved  in  400  parts  of  10  %  caustic  soda 
solution  and  the  mixture  is  introduced  into  a  lead-coated, 
steam-jacketed  autoclave  provided  with  an  efficient  stirrer. 
Ethyl  chloride,  70  parts  (i^  mol.),  is  introduced,  and  the 
mixture  heated  under  pressure  at  90°-ioo°  for  7-8  hours. 
The  ^-nitrophenetol  is  filtered  off  after  cooling,  washed  first 
with  5  %  caustic  soda  solution,  to  remove  any  unchanged 
^-nitrophenol,  and  then  with  water.  It  is  passed  on  for 
reduction  in  the  next  stage  without  being  dried. 

Reduction  of  p-Nitrophenetol  to  p-Phenetidine. — This 
operation  is  carried  out  in  a  similar  way  to  that  of  the 
reduction  of  nitrobenzene  to  aniline,  with  iron  and  hydro- 
chloric acid.  A  cast-iron  still  is  employed,  which  is  provided 
with  stirring  gear,  a  manhole  for  the  introduction  of  the 
materials,  and  a  pipe  for  admitting  live  steam. 

A  mixture  of  1000  parts  of  ^-nitrophenetol,  2000  parts 
of  water,  and  60  parts  of  hydrochloric  acid  (sp.gr.  1-14)  is 
introduced  into  the  vessel  and  heated  by  direct  steam  to 
about  60°.  With  continuous  stirring  100  Ibs.  of  iron 
turnings  are  introduced,  followed  by  a  further  900  Ibs.  in 
portions  over  a  period  of  3-4  hours.  The  temperature  is 
then  raised  gradually  to  about  90°,  at  which  it  is 
maintained  until  the  reduction  is  completed.  The  whole 
operation  occupies  about  8  hours.  Heating  and  stirring 
are  then  stopped,  and  the  supernatant  aqueous  liquor 
siphoned  off  from  the  iron-ironoxide-phenetidine  sludge. 
A  portion  of  the  liquor  is  utilised  for  a  further  reduction  ; 
the  remainder  is  either  discarded — the  amount  of  phenetidine 
contained  in  it  being  very  small — or,  if  a  separate  steam 
generator  is  employed,  is  vaporised  and  used  either  in 
the  heating  up  of  another  charge  or  in  the  removal  of  the 
phenetidine  from  the  sludge.  This  is  effected  by  distillation 
in  a  current  of  superheated  steam,  at  i6o°-i8o°,  at  which 
temperature  phenetidine  is  readily  volatilised.  It  distils 
over  as  a  clear  colourless  oil,  which  is  separated  mechanically 
from  the  aqueous  layer  of  the  distillate. 

The  reduction  of  ^-nitrophenetol  may  also  be  carried  out 


ANTIPYRETICS  AND  ANALGESICS         119 

by    means    of    sodium    sulphide,    the    reaction   proceeding 
according  to  the  following  equations.     (D.  R.  P.  139568.) 

R-NO2+Na2S+H2O  ->  R'NH2+Na2SO3  (at  110°) 
4R-NO2  +  6Na2S  +7H2O-»4R-NH2  +3Na2S2O3  +6NaOH 
(at  lower  temperatures). 

Crystallised  sodium  sulphide  (Na2S*ioH2O),  2\  parts, 
is  fused  in  a  jacketed  iron  vessel,  provided  with  a  stirrer 
and  a  reflux  condenser,  and  heated  to  boiling  point  (108°- 
110°).  Nitrophenetol,  i  part,  is  added,  and  the  mixture 
vigorously  boiled.  The  reduction  is  complete  when  a  test 
portion,  after  acidification  with  hydrochloric  acid,  affords  no 
extract  to  ether.  The  phenetidine  may  either  be  distilled 
with  superheated  steam,  or  separated  mechanically  from  the 
sulphite  liquor  and  purified  by  direct  distillation  in  vacuo. 

pig.  15.) 

This  method  of  reduction  is  more  costly,  in  materials, 
than  the  one  with  iron  and  acid,  but  the  isolation  of  the 
product  is  attended  by  fewer  mechanical  difficulties. 

Acetylation  of  ^-Phenetidine. — The  preparation  of  acet- 
/>-phenetidine  (phenacetin)  is  similar  to  that  of  acetanilide. 
Equal  weights  of  distilled  phenetidine  and  glacial  acetic 
acid  are  heated  together  at  the  boiling  point  of  the  mixture 
in  an  enamelled  or  silver-lined  still  until  the  diazo  test  shows 
that  it  is  free  from  unchanged  amine,  which  should  be  in 
about  10  hours.  As  much  of  the  excess  of  acetic  acid  as  will 
distil  over  in  vacuo  at  about  120°  is  then  recovered  and 
the  residue  dissolved  in  boiling  water,  from  which,  after 
treatment  with  charcoal,  filtering,  and  cooling,  greyish- 
tinted  crystals  of  phenacetin  separate.  These  are  centri- 
fuged,  and  washed  with  water.  It  is  purified  by  recrystal- 
Hsation  from  boiling  water  or  from  60  %  alcohol,  using 
animal  charcoal  to  decolourise,  and  adding  a  little  SO2 
to  the  filtered  solution,  to  prevent  oxidation  during  crystal- 
lisation. 

From  p-Acetaminophenol. — Preparation  of  para-acetamino- 
phenol. — The  preparation  of  para-aminophenol  by  the  re- 
duction of  para-nitrophenol,  using  tin  and  hydrochloric  acid, 


120         ORGANIC  MEDICINAL  CHEMICALS 

has  been  described  by  Paul  (Zeits.  angew.  Chem.  1896,  9,  594). 
A  cheaper  method  is  to  employ  sodium  sulphide.  One  part 
of  ^-nitrophenol  is  boiled  with  3  parts  of  crystallised  sodium 
sulphide  for  an  hour,  when  reduction  is  complete.  The 


product  is  poured,  with  stirring,  into  a  slight  excess,  5  parts, 
of  hydrochloric  acid  solution  (sp.gr.  1*14).  The  mixture  is 
heated  to  boiling  point  and  filtered.  On  cooling,  />-amino- 
phenol  hydrochloride  crystallises  out  and  is  separated. 
The  filtrate,  after  being  concentrated  until  salt  commences 


ANTIPYRETICS  AND  ANALGESICS         121 

to  separate,  affords  on  cooling  a  further  small  crop  of  the 
hydrochloride. 

Another  method  for  the  preparation  of  />-aminophenol 
consists  in  reducing  para-nitrosophenol,  also  with  sodium 
sulphide. 

p-Nitrosophenol. — In  a  wooden  vat  provided  with  an 
efficient  stirrer  is  prepared  a  solution  of  520  Ib.  of  sodium 
nitrite  in  100  galls,  of  water.  This  is  cooled  to  +5°  by 
the  addition  of  ice  and  to  it  added  slowly,  simultaneously, 
and  in  equivalent  quantities,  a  cold  solution  of  560  Ib.  of 
phenol  in  56  Ib.  of  water,  and  400  Ib.  of  sulphuric  acid 
cone.,  diluted  with  800  parts  of  ice.  The  temperature  is 
kept  between  4°  and  7°  by  the  addition  of  ice.  After  the 
addition  is  completed  stirring  is  continued  for  an  hour, 
after  which  10  cwt.  of  salt  is  dissolved  in  the  solution. 
The  precipitated  nitrosophenol  is  then  centrifuged  or  strained 
off  and  washed  with  salt  solution.  It  is  reduced  by  being 
added  gradually  to  a  stirred  mixture  of  15  cwt.  of  sodium 
sulphide  cryst.  and  120  galls,  of  water.  The  temperature 
during  addition  of  the  nitrosophenol  is  not  allowed  to  rise 
above  30°  ;  after  all  has  been  added  it  is  raised  to  70°. 
The  reduction  liquor  is  then  allowed  to  flow,  with  stirring, 
into  160  galls,  of  25  %  hydrochloric  acid.  The  solution, 
which  contains  ^-aminophenol  hydrochloride,  is  filtered, 
after  cooling,  and  the  base  precipitated  by  addition  of  soda 
ash.  It  is  pressed  off,  washed  with  water,  and  purified  by 
dissolving  it  in  hot  diluted  sulphuric  acid,  from  which  crystals 
of  pure  aminophenol  sulphate  separate  on  cooling.  This 
salt  is  only  sparingly  soluble  in  cold  water.  The  filtrate, 
after  addition  of  more  sulphuric  acid,  is  employed  for 
dissolving  a  further  quantity  of  the  base. 

Acetylation  of  p- Aminophenol. — An  amount  of  the  crystal- 
lised hydrochloride  or  sulphate  containing  100  parts  of 
^-aminophenol  is  mixed  with  water  and  the  quantity  of 
soda  ash  necessary  to  liberate  the  base  is  added.  The  mixture 
is  well  stirred,  cooled  to  10°,  and  100  parts  of  acetic 
anhydride  (100  %)  added,  in  small  quantities  at  a  time, 
the  temperature  being  kept  at  about  10°  by  the  addition 


122         ORGANIC  MEDICINAL  CHEMICALS 

of  ice.  Stirring  is  continued  for  an  hour  after  the  anltydride 
has  all  been  added,  after  which  the  precipitate  of  para- 
acetaminophenol  is  centrifuged  off  and  washed  with  a  little 
water  or  salt  solution.  The  filtrates  are  neutralised  with 
sodium  carbonate,  and  any  base  that  is  precipitated  reacetyl- 
ated  with  another  batch.  The  liquors  may  be  evaporated 
down  and  the  acetic  acid  recovered. 

The  acetaminophenol  should  be  practically  colourless 
and  should  melt  at  i67°-i69°. 

Ethylation  of  ^-acetaminophenol. — A  quantity  of  moist 
^-acetaminophenol,  containing  151  parts  of  the  dry  material 
(imol.),  120  parts  of  ethyl  bromide  (ly^  mol.),  40  parts 
of  caustic  soda  (i  mol.),  and  400  parts  of  alcohol  (S.V.M.), 
and  recovered  alcohol  from  a  previous  batch  are  refluxed 
together  for  8  hours.  Excess  of  ethyl  bromide  and  alcohol 
are  then  distilled  off  and  the  residue  dissolved  out  in  boiling 
water.  The  solution,  after  nitration,  is  allowed  to  cool. 
Phenacetin  crystallises  out,  a  pinkish-grey  product,  and  is 
centrifuged  off.  From  the  liquors  alcohol  is  recovered  by 
distillation,  and  they  are  then  evaporated  down  for  the 
recovery  of  sodium  bromide. 

The  crude  phenacetin  is  purified  by  a  further  crystallisa- 
tion from  water,  or  from  90  %  alcohol  (S.V.M.),  charcoal  and 
SO2  being  employed  as  decolourising  agents. 

Phenacetin  is  usually  sold  in  the  form  of  white  glistening 
crystalline  scales.  M.p.  134°.  It  dissolves  in  1700  parts 
of  water,  when  cold,  and  in  50  parts  of  boiling  water.  In 
cold  90  %  alcohol,  it  is  soluble  to  the  extent  of  i  in  21  ;  and 
in  cold  60  %  alcohol,  i  in  100. 

Phenacetin  should  dissolve  without  the  formation  even 
of  a  transitory  colour  in  concentrated  sulphuric  acid.  A 
mixture  of  0*3  gram  with  i  c.c.  of  alcohol  and  3  c.c.  of  water 
should  not  acquire  a  red  colour  on  boiling  with  i  drop  of 

N 

—  iodine   solution    (absence   of  phenetidine) .     No   residue 

should  be  left  after  ignition  of  a  sample. 

Phenacetin  is  a  most  widely  used  antipyretic  and  anal- 
gesic, and  has  a  notable  freedom  from  injurious  action. 


ANTIPYRETICS  AND  ANALGESICS         123 

It  does  not  produce  nausea,  and  has  but  a  slight  depressant 
action.     Phenacetin  is  administered  for  the  relief  of  pain 
in  neuralgia,  rheumatism,  locomotor  ataxia,  etc.,  and  as  an 
antipyretic  in  influenza  and  in  fevers  generally. 
LACTOPHENIN  (lyactyl  phenetidine) . 

C2H5O<f  ~\NH(COCHOHCH3).     209. 


The  following  methods  of  preparation  of  this  substance  have 
been  described  :  by  heating  phenetidine  lactate  (D.  R.  P. 
70250) ;  by  condensing  lactamide  with  ^-phenetidine  (D.  R.  P. 
81539)  ;  by  treating  with  sodium  acetate  the  condensation 
product  of  ^-phenetidine  and  a-brompropionyl  bromide 
(D.  R.  P.  85212)  ;  and  by  ethylating  lactyl  ^-aminophenol 
(D.  R.  P.  90595).  Of  these  the  first  is  the  only  one  likely  to 
be  employed  in  practice. 

Ten  kilos  of  phenetidine  lactate  are  heated  slowly  to  180° 
in  an  enamelled  vessel,  in  vacuo,  and  maintained  at  this 
temperature  until  water  is  no  longer  evolved.  The  reaction 
mixture  is  poured  into  200  litres  of  water,  which  is  boiled 
until  solution  is  complete.  Charcoal  is  employed  to  de- 
colourise the  solution,  from  which,  after  filtration  and  cooling, 
the  lactyl  ^-phenetidine  crystallises  out.  If  still  coloured 
it  is  recrystallised  from  dilute  alcohol,  again  with  the  use  of 
charcoal.  lyactophenin  is  a  white  crystalline  powder. 
M.p.  Ii7°-ii8°.  It  dissolves  in  55  parts  of  boiling,  and  is 
sparingly  soluble  in  cold,  water. 

The  solution  in  pure  sulphuric  acid  should  be  colourless, 
lyactophenin  should  give  no  reaction  for  para-phenetidine, 
which  is  tested  for  by  boiling  5  c.c.  of  a  solution  in  25  % 

N 

alcohol  with  i  drop  of   -  iodine  solution,  when  no  red  coloura- 
10 

tion  should  be  developed. 

lyactophenin  is  antipyretic  and  analgesic,  similar  in  action 
to  phenacetin  but  stated  to  have  a  more  marked  hypnotic 
action  and  not  to  affect  either  the  circulation  or  the  respira- 
tion. It  is  employed  in  migraine,  erysipelas,  nervous 
headache,  and  the  neuralgia  of  influenza.  It  is  stated 
to  attain  its  maximum  activity  in  a  very  short  time, 


124         ORGANIC  MEDICINAL   CHEMICALS 

owing  to  its  being,  to  a  large  extent,   absorbed  from  the 
stomach. 

ANTIPYRINE  (Phenazone,    analgesin),  i  phenyl-   2.3  di- 
methyl- 5-pyrazolone  CnH12ON2.     188. 


N 


CH3'N     CO 

CH3-C=CH 

Antipyrine  is  prepared  by  condensing  acetoacetic  ester  with 
phenyl  hydrazine,  and  methylating  the  resulting  1*3  phenyl  - 
methy  Ipy  r  azolone  . 


rcH3-c-CH,—  cooc2HB-| 

CH3COCH2—  COOEt+NH2-NH-C6HB->  ||  +H2O 

N—  NHC.H. 

I3O  TOR  22O  -J 


CH3-C— CH2— CO  CH8C=CH— CO  CH3— C=CH— CO 

N—       -rtCeH/  NH N'CflH5       *   CH.-N NC6H5 

174  188 

D.  R.  P.  26429  ;  E.  P.  3097/1884  ;  Ber.  16,  2597,  17,  549> 
2037,  25,  759 ;  Ann.  238,  147. 

It  has  also  been  made,  in  one  operation,  by  condensing 
equivalent  quantities  of  acetoacetic  ester  and  methyl-phenyl 
hydrazine  C6H5NH'NHCH3  (D.  R.  P.  40377),  but  the  yields 
afforded  by  this  method  are  stated  to  be  small. 

Another  patented  process  consists  of  condensing  phenyl 
hydrazine  with  /3-chloropropionic  acid,  to  phenyldihydro- 
pyrazolone 

C6H5N 
NH/XCO 

I         I 
CH2— CH2 

and  oxidising  this  with  mercuric  oxide  to  phenylpyrazolone 

C6H5N 
NH/XCO 

i        ! 
CH=CH 

which  affords  antipyrine  when  methylated  (D.  R.  P.  53834)- 


ANTIPYRETICS  AND  ANALGESICS         125 

Protection  was  refused  for  a  method  whereby  antipyrine 
was  claimed  to  be  formed  in  one  operation,  by  heating  tinder 
pressure  a  mixture  of  phenyl  hydrazine,  acetoacetic  ester, 
sodium  methyl  sulphate,  sodium  iodide,  and  methyl  alcohol 
containing  a  little  hydriodic  acid. 

According  to  D.  R.  P.  69883,  i-phenyl-2-methyl-5-pyra- 
zolone  can  be  obtained  by  combining  phenyl  hydrazine  and 
oxalacetic  ester,  methylating  the  product  (phenylpyrazolone 
carbonic  acid  ester),  saponifying  and  splitting  off  carbon 
dioxide  ;  alternatively  the  condensation  product  (2)  is 
saponified,  CO2  split  off,  and  the  resulting  body  methylated. 


CH, 

->  C6H5N—  NH—  C—  COOEt  ->  C6H5N—  N—  C—  COOEt 

1  I'  I  II 

CO  -  CH  CO  -  CH 

(2)  (3) 

CH3  CH3  CH3 

->  C6H5N—  N—  C—  COOH  ->  C6H6N—  N—  CH  -»  CeH6N—  N—  C—  CH3 

CO  -  CH  CO  -  CH  CO  -  CH 

(4)  (5)  Antipyrine. 

From  Phenyl  Hydrazine  and  Acetoacetic  Ester  (seeD.  R.  P. 
26429).  —  Pure  acetoacetic  ester,  120  kgs.,  mixed  with  12 
kgs.  of  85  %  alcohol,  is  allowed  to  flow,  with  cooling  and 
stirring,  into  100  kgs.  of  phenyl  hydrazine  which  has  been 
freshly  distilled  in  vacuo  and  dissolved  in  benzene.  The  react- 
ing substances  are  in  practically  equivalent  proportions,  the 
phenyl  hydrazine  being  in  very  slight  excess.  It  is  stated 
that  an  excess  of  either  is  detrimental  ;  if  of  the  ester,  a 
yellow-coloured  pyrazolone  is  produced  which  gives  rise 
to  an  antipyrine  that  becomes  coloured  by  the  action  of  light  ; 
if  of  phenyl  hydrazine,  the  required  condensation  product 
is  oxidised  to  a  fo's-phenylmethylpyrazolone.  The  mixture 
is  boiled  for  a  short  time  under  a  reflux,  the  solvent 
then  distilled  off  and  the  residue  is  allowed  to  cool,  when  a 
crystalline  mass  of  i-phenyl-3-methyl-5-pyrazolone  separates. 
It  is  dissolved  in  hot  water,  filtered  from  coloured  impurities, 


126         ORGANIC  MEDICINAL   CHEMICALS 

allowed  to  crystallise,  and  recrystallised  from  alcohol. 
M.p.  127°. 

The  phenyl-methyl-pyrazolone  is  methylated  with  methyl 
chloride  or  methyl  bromide  in  methyl  alcoholic  solution, 
at  90°-ioo°,  a  slight  excess  of  the  methylating  agent 
being  employed.  This  operation  is  conducted  under  pressure 
in  an  autoclave  fitted  with  stirring  gear.  After  distilling 
off  the  alcohol  the  reaction  product  is  dissolved  in  water, 
made  slightly  alkaline  with  sodium  hydroxide  solution, 
the  alcohol  and  unchanged  methylating  agent  are  recovered, 
and  the  antipyrine  is  extracted  with  benzene.  It  is  purified 
by  recrystallisation,  first  from  benzene,  then  from  water, 
charcoal  being  employed  to  decolourise  the  solutions. 

Antipyrine  is  sold  in  the  form  of  colourless  crystalline 
scales  or  as  a  white  powder.  It  is  odourless,  and  possesses  a 
slightly  bitter  taste.  M.p.  113°. 

Soluble  in  ij  parts  of  water,  very  readily  also  in  alcohol, 
chloroform,  and  benzene.  The  aqueous  solution  should  be 
neutral  to  litmus  and  should  not  be  affected  by  hydrogen 
sulphide  solution. 

Antipyrine  is  a  valuable  analgesic  and  antipyretic.  It  is 
employed  in  neuralgia,  gout,  rheumatism,  and  other  painful 
affections,  and  is  used  to  reduce  temperature  in  febrile  disease. 

It  is  stated  to  be  a  good  uterine  sedative  ;  also  to  relieve 
sickness.  Antipyrine  should  not  be  administered  to  subjects 
of  cardiac  weakness,  on  account  of  its  depressant  effect. 
To  counteract  this  it  is  frequently  prescribed  in  conjunction 
with  caffeine. 

Combinations  with  antipyrine  which  have  found  consider- 
able acceptance  are  antipyrine  salicylate  —  salipyrine,  and 
chloral  and  antipyrine  —  hypnal. 

PYRAMIDON  (4  -  dimethylamino-i-phenyl-2.3-dimethyl 
pyrazolon)  C13H17ON3.  231. 


N 
CH3-NXXCO 

I         I 
CH3-C=CN(CH3)2 


ANTIPYRETICS  AND  ANALGESICS         127 

Pyramidon  is  obtained  by  the  following  series  of  reactions:  — 
Antipyrine  is  converted  into  its  nitroso  derivative,  which  is 
reduced  to  the  corresponding  amino  compound.  This  is 
methylated,  either  by  treatment  with  a  methyl  halide,  or 
by  condensation  with  chloracetic  acid  followed  by  subse- 
quent elimination  of  CO2. 


N  N 

CH3N/XCO  ->        C 

II  II 

CHC=CH  CH3C=C'NO 


N  N 

CH3'N/XCO          ->    CH3-N/XCO 


'C=C' 


CH3-C=CN(CH3)2 

Nitroso-antipyrine  is  prepared  (Ann.  238,  212)  by  dis- 
solving antipyrine  in  one  molecular  proportion  of  dilute 
aqueous  hydrochloric  acid  and  treating,  whilst  cooling  and 
stirring,  with  the  calculated  quantity  (i  mol.)  of  sodium 
nitrite.  The  nitroso  compound  separates  as  a  green  crystal- 
line precipitate,  which  is  filtered  off. 

Nitroso-antipyrine  is  slightly  soluble  in  water,  alcohol,  or 
chloroform  ;  it  dissolves  in  acids,  and  is  reprecipitated  on 
neutralisation.  On  heating  it  decomposes  at  200°. 

Amino-antipyrine  (D.  R.  P.  71261) 

C6H5 

N 


CH3-C=C-NH2 

Nitroso-antipyrine,  100  parts,  is  suspended  in  a  mixture  of 
100  parts  of  water,  500  parts  of  alcohol,  and  200  parts  of 
10  %  acetic  acid  and  reduced  by  the  gradual  addition  of  zinc 
dust.  The  temperature  is  kept  below  40°  by  cooling. 


128         ORGANIC  MEDICINAL   CHEMICALS 

When  the  nitroso  body  has  all  disappeared  and  the 
solution  remains  only  slightly  coloured,  48  parts  of  benzalde- 
hyde,  dissolved  in  200  parts  of  10  %  acetic  acid  con- 
taining 20  %  alcohol,  are  added,  when  the  benzylidene 
compound  of  amino-antipyrine  separates.  After  standing 
for  some  time  the  crystals  are  filtered  off,  washed  first  with 
50  %  alcohol,  then  with  water  acidified  with  acetic  acid  (to 
retrieve  the  zinc  acetate),  and  dried.  The  product  is 
recrystallised  from  alcohol,  from  which  it  separates  in  the 
form  of  yellow,  shining  leaflets.  M.p.  173°. 

The  benzylidene  compound  is  decomposed  into  benzalde- 
hyde  and  amino-antipyrin  hydrochloride  by  agitation  with 
dilute  hydrochloric  acid  and  benzene.  The  acid  layer  is 
separated,  neutralised,  and  concentrated ;  then,  after 
cooling,  made  alkaline  with  sodium  carbonate  and  extracted 
with  benzene  or  toluene,  which  removes  the  base. 

Amino-antipyrine  crystallises  in  yellow  needles. 
M.p.  109°. 

Methylation  of  Amino-antipyrine. — (a)  With  methyl  iodide 
(D.  R.  P.  90959). — According  to  the  patent  specification 
i  kg.  of  amido-antipyrine  is  heated  for  i  hour  at  90°  with 
i  kg.  of  methyl  alcohol  and  i  kg.  of  methyl  iodide.  The 
alcohol  is  distilled  off,  and  the  residue  dissolved  in  water,  made 
alkaline,  and  extracted  with  benzene.  The  solvent  is  distilled 
off  and  the  pyramidon  recrystallised  from  light  petroleum. 

In  D.  R.  P.  111724  it  is  stated  that  in  carrying  out  the 
methylation  as  above  the  quaternary  methiodide  is  always 
produced  together  with  the  required  tertiary  base.  This  is 
converted  into  pyramidon  by  either  of  the  following 
methods : — 

(1)  10  parts  of  dimethylamino-phenylpyrazolone   meth- 
iodide are  heated  under  pressure  with  40  parts  of  alcohol 
at  140°  for  i  day.     After  cooling,  any  unchanged  methiodide 
is  filtered  off  and  the  pyramidon  extracted,  after  removal  of 
alcohol  and  alkalisation,  with  benzene. 

(2)  The  methiodide  is  heated  with  an  equivalent  quantity 
of  sodium  acetate,  in  aqueous  solution,  at  I5o°-i6o°  for 
i  day. 


ANTIPYRETICS  AND  ANALGESICS  129 

Alcohol  may  be  used  by  preference,  the  reaction  being 
carried  out  at  140°.  The  pyramidon  is  extracted  with 
benzene,  as  above.  It  is  to  be  noted  in  connection  with  this 
methylation,  that  considerably  less  than  the  theoretical 
quantity  (2  mols.)  of  methyl  iodide  is  stated  to  be  used. 
At  the  same  time  it  seems  unlikely  that,  at  the  tem- 
perature given,  methyl  alcohol  would  act  as  a  methylating 
agent. 

(b)  With  chloracetic  acid  (D.  R.  P.  144393).-—  9-45  kgs. 
of  chloracetic  acid  are  dissolved  in  25  litres  of  water, 
and  gradually  neutralised  with  16*8  kgs.  of  sodium  car- 
bonate cryst.  Amino-antipyrine,  10-15  kgs.,  is  then  added, 
and  the  mixture  boiled,  under  a  reflux  condenser,  for  2 
hours.  It  is  then  cooled  to  20°  and  treated  with  2-37 
kgs.  of  chloracetic  acid,  4-3  kgs.  of  sodium  carbonate,  and 
2  -i  kgs.  of  sodium  bicarbonate,  and  boiled  for  a  further  2 
hours. 

The  completion  of  the  reaction  is  ascertained  by  the 
following  tests  : 

Absence  of  amino-antipyrine.  —  A  small  test  portion  is 
diluted  with  water,  cooled  with  ice,  and  treated  first  with 
HC1  and  then  with  sodium  nitrite  solution.  Excess  of 
nitrous  acid  is  destroyed  by  the  addition  of  urea,  and  the 
solution  then  added  to  an  alkaline  aqueous  solution  of 
R  salt,  when  only  a  faint  red  colouration,  or  none,  should 
be  produced. 

Test  for  absence  of  the  monoacetic  acid  derivative.  — 
Several  cubic  centimetres  of  the  solution  are  made  faintly 
acid  with  acetic  acid,  heated  to  50°  and  extracted  with 
chloroform,  in  which  any  mono-compound  will  be  dissolved 
and  obtained  on  evaporation  of  the  solvent. 

d  iHi  !N20  -NH2  +2CH2ClCOONa 


The  total  reaction  mixture  is  now  transferred  to  an 
enamelled  autoclave,  treated  with  2*85  kgs.  of  24  %  hydro- 
chloric acid  (3!  mols.)  and  heated  for  10-12  hours  at  120° 
i.  9 


130         ORGANIC  MEDICINAL  CHEMICALS 

to  140°.     Considerable   pressure   is  present  after  cooling, 
owing  to  the  liberation  of  CO2.  , 


After  cooling,  25  kgs.  of  caustic  soda  are  added,  when  a  mass 
of  white  crystals  separates.  These  are  filtered  off  and  the 
filtrate  extracted  three  times  with  benzene.  The  crystals 
also  are  dissolved  in  the  benzene,  the  solution  is  dried  over 
potassium  carbonate  and  the  solvent  distilled  off.  The 
pyramidon  thus  obtained  is  purified  by  recrystallisation 
from  light  petroleum. 

As  a  modification  of  the  above  method  i  molecular 
proportion  of  amino-antipyrine,  2\  mols.  of  chlor-  or  brom- 
acetic  acid  and  2\  mols.  of  crystallised  sodium  acetate  are 
heated  together  for  2  hours  at  100°,  followed  by  i  hour  at  120°. 
The  mixture  is  then  diluted  with  2-3  volumes  of  water, 
treated  with  3^  mols.  of  sulphuric  acid,  and  saturated  with 
salt,  when  the  diacetic  acid  derivative  comes  out  in  the  form 
of  a  thick,  gummy  syrup.  This  is  separated,  and  boiled  with 
i  mol.  of  sulphuric  acid  and  6  vols.  of  water,  until  evolution 
of  CO2  has  ceased.  The  pyramidon  is  then  precipitated,  as 
in  the  former  example,  by  saturating  the  solution  with 
caustic  soda. 

Pyramidon  is  a  white,  or  yellowish-white,  crystalline 
powder.  M.p.  108°.  It  dissolves  in  n  parts  of  cold  water, 
and  is  readily  soluble  in  alcohol,  ether,  and  benzene. 

Pyramidon  is  antipyretic  and  analgesic,  like  antipyrine, 
and  is  effective  in  smaller  doses.  It  is  claimed  to  be  compara- 
tively free  from  harmful  action  on  the  blood,  heart,  or  kidneys. 

It  is  employed  in  acute  febrile  conditions  incident  to 
typhoid  fever,  pneumonia,  and  erysipelas  ;  also  in  treatment 
of  high  temperature  caused  by  tuberculosis.  It  has  also 
been  used  in  asthma  of  reflex  origin. 

BENZOIC  ACID  C7H6O2.  122.—  (C6H6COOH).  Benzoicacid 
is  formed  during  the  production  of  benzaldehyde  from  toluene 
(see  Barnett,  Coal  Tar  Dyes  and  Intermediates,  p.  79),  and  the 
commonly  employed  method  of  manufacture  is  as  follows  :  — 


ANTIPYRETICS  AND  ANALGESICS         131 

Chlorine  passed  through  lead  pipes,  is  bubbled  through 
rectified  toluene  heated  to  110°,  in  an  earthenware-lined 
or  lead-lined  cast-iron  vessel,  until  it  possesses,  at  15°,  a 
specific  gravity  of  1-35.  The  product  consists  mainly  of 
benzotrichloride  C6H5CC13,  admixed  with  some  benzal 
chloride  C6H5CHC12.  Iron  must  be  carefully  excluded  from 
the  apparatus,  as  ferric  chloride  acts  as  a  catalyst  and 
causes  the  chlorine  to  enter  the  nucleus,  with  formation  of 
chlorotoluenes.  It  is  necessary  that  both  toluene  and  chlorine 
should  be  dry,  since  moisture  also  facilitates  nuclear  sub- 
stitution. The  hydrochloric  acid  which  is  evolved  and 
volatilised  toluene  are  condensed  in  earthenware  condensers 
and  washing  towers. 

Under  the  above  conditions  it  is  not  necessary  to  employ 
a  carrier,  for  which  phosphorus  trichloride  has  been  recom- 
mended, or  to  conduct  the  chlorination  in  ultra-violet  light, 
though  the  latter  procedure  is  said  to  be  advantageous  in 
accelerating  the  reaction. 

Sixty  kgs.  of  benzotrichloride  are  added  to  200  kgs.  of 
milk  of  lime,  containing  34  kgs.  of  CaO,  and  20  grams 
of  iron  powder,  in  a  cast-iron  vessel,  fitted  with 
stirring  gear  and  connected  to  a  condenser.  The  mix- 
ture is  heated  by  direct  steam  to  50°,  at  which  point 
the  temperature  rises  spontaneously ;  the  water  and 
benzaldehyde  commence  to  distil  and  are  allowed  to  reflux. 
When  the  reaction  commences  to  slow  down,  direct  steam  is 
again  applied,  and  the  benzaldehyde  is  distilled  away. 

The  operation  takes  9-10  hours.  The  residual  liquid  is 
filtered,  transferred  to  a  wooden  vat  fitted  with  a  stirrer,  and 
acidified  with  hydrochloric  acid  to  precipitate  the  benzoic 
acid.  This  is  filtered  off  after  cooling  and  purified  by 
recrystallisation  from  water,  or  by  sublimation  after  drying. 
In  Fig.  16  is  shown  a  plant  for  the  sublimation  of  benzoic 
acid. 

Another  method  for  the  preparation  of  benzoic  acid, 
based  on  the  formation  and  oxidation  of  benzyl  alcohol, 
is  given  in  B.  P.  116348/1917.  Toluene,  92  parts  by 
weight,  is  chlorinated  at  its  boiling  point  until  the  density 


132 


ORGANIC  MEDICINAL   CHEMICALS 


at  15°  is  i-ii,  the  bulk  of  the  product  being  at  this  stage 
benzyl  chloride.  It  is  then  boiled,  in  an  iron  vessel  provided 
with  a  reflux  condenser,  for  2  hours,  with  a  quantity  of  lime 
or  caustic  soda  equivalent  to  the  chlorine  used,  e.g.  400  parts 
of  20  %  caustic  soda.  A  solution  of  sodium  or  calcium 
hypochlorite,  e.g.  2030  parts  of  calcium  hypochlorite  solution 
containing  7  %  of  available  chlorine,  is  added  in  the  course 
of  3  hours,  and  stirring  is  continued  for  a  further  3  hours, 


FIG.  1 6. — Benzole  acid  sublimer. 

after  which  the  mixture  is  distilled  until  free  from  toluene. 
The  residual  alkali  benzoate  solution  is  filtered,  and  the 
benzoic  acid  precipitated  with  hydrochloric  acid,  dried  and 
volatilised.  The  important  object  to  attain  in  manufacturing 
benzoic  acid  for  pharmaceutical  purposes  is  freedom  from 
chloro  compounds. 

Benzoic  acid  forms  colourless,  feathery,  almost  odour- 
less crystals,  melting  at  121*4°.     It  is  soluble  in  390  parts  of 


ANTIPYRETICS  AND  ANALGESICS         133 

cold,  and  in  12  parts  of  boiling  water  ;  in  12  parts  of  benzene, 
and  in  2|  parts  of  90  %  alcohol.  It  should  be  free  from 
chloro  compounds,  detected  by  igniting  a  portion  with 
chlorine-free  lime  or  calcium  carbonate,  dissolving  the  residue 
in  nitric  acid  and  adding  silver  nitrate  solution.  A  solution 
in  pure  concentrated  sulphuric  acid  should  not  become 
darker  than  light  brown  on  warming,  and  the  colour  of  2 
drops  of  i  %  potassium  permanganate  solution  should  not 
be  immediately  destroyed  by  0*2  gram  of  the  acid  suspended 
in  10  c.c.  of  water. 

Benzoic  acid  is  employed  as  a  disinfecting  expectorant 
in  cases  of  phthisis  and  chronic  bronchitis ;  also  in  chronic 
cystitis,  to  acidify  and  disinfect  alkaline  and  decomposing 
urine.  It  is  excreted  partly  as  hippuric  acid  but  partly 
unchanged.  It  is  frequently  administered  in  the  form  of 
its  sodium  or  ammonium  salt,  since  these  are  less  irritating 
to  the  alimentary  canal.  The  acid  also  possesses  antipyretic 
properties,  and  is  prescribed  in  acute  rheumatism. 

OH 

SALICYLIC  ACID  <^)>COOH  (orthohydroxybenzoic 
acid).  138. — For  the  preparation  of  salicylic  acid,  sodium 
phenate  is  combined  with  carbon  dioxide,  forming  sodium 
phenyl  carbonate,  which,  on  heating,  is  converted  into 
sodium  salicylate. 

C6H6ONa+C02    ->    C6H6OCOONa     -> 

The  operations  comprise  :— 

(1)  The  preparation  of  dry  sodium  phenate. 

(2)  Carbonation  and  conversion  to  sodium  salicylate. 

(3)  The  separation  and  purification  of  salicylic  acid. 

It  is  essential  that  the  sodium  phenate  should  be  finely 
powdered  and  that  it  should  be  absolutely  free  from  moisture. 
As,  when  hot,  it  readily  oxidises  in  the  presence  of  air,  it  is 
advisable  to  conduct  the  operation  of  drying  and  powdering 
in  a  shallow  vacuum  pan  fitted  with  powerful  stirring  gear, 
similar  to  that  shown  in  Figs.  17  and  18.  In  order  to 
obviate  the  risk  of  the  dried  phenate  absorbing  moisture 


134         ORGANIC  MEDICINAL  CHEMICALS 

when  handled,  it  is  desirable  to  carry  out  the  drying  and 
powdering  in  a  vessel  so  constructed  that  the  dried  product 
can  be  transferred,  without  exposure,  to  the  vessel  in  which 
the  carbonation  is  to  be  conducted.  The  most  suitable 
type  of  plant  for  the  latter  purpose  is  a  horizontal  jacketed 
steel  autoclave,  provided  with  powerful  rotating  stirrers 
which  scrape  the  sides  (Figs.  19  and  20).  An  inlet  pipe  for 


FIG.  17. — Vacuum  dryer. 

the  introduction  of  the  carbon  dioxide  is  required  ;  also  an 
outlet  to  a  condenser  and  receiver  (provided  with  a  sight 
glass)  which  is  connected  with  a  vacuum  pump,  so  that  the 
phenate  may  be  submitted  to  a  final  drying  before  carbona- 
tion commences.  Either  cold  water  or  steam  at  60  Ibs. 
pressure  can  be  circulated  through  the  jacket. 

Phenol  is  dissolved  in  the  calculated  quantity  (i  mol.) 
of  40  %  caustic  soda  solution  and  the  mixture  introduced 


ANTIPYRETICS  AND  ANALGESICS 


135 


into  the  vacuum  pan,  in  which  it  is  evaporated  to  dry  ness 
in  vacuo,  the  stirrers  being  kept  continuously  in  motion. 


FIG.  1 8. — Vacuum  dryer  and  carbonator. 

Heating,  to  a  temperature  of  I20°-i30°,  is  continued  for 
about  an  hour  after  the  condensation  of  water  has  ceased. 
The  sodium  phenate  is  now  in  the  form  of  a  fine  powder  and  is 


136         ORGANIC  MEDICINAL  CHEMICALS 

transferred  while  still  hot  to  the  autoclave,  the  latter  is 
rendered  vacuous  and  the  stirrer  started  ;  the  vacuum  valve 
is  then  closed  and  dry  carbon  dioxide  is  introduced.  Absorp- 
tion takes  place  rapidly,  with  rise  of  temperature.  The  gas 
is  passed  in  until  the  gauge  shows  a  positive  pressure  of 
3  atmospheres.  Steam  is  then  turned  on  and  the  temperature 
raised  to  I20°-i30°,  more  gas  being  introduced  to  maintain 
the  pressure.  Heating  is  continued  for  3  hours  after  ab- 
sorption is  complete,  after  which  time  it  is  stopped  and  the 
cold  water  circulated  again,  to  reduce  the  temperature 
somewhat.  The  excess  of  CO2  is  used  in  the  carbonation 


FIG.  19. — High-pressure  autoclave  for  carbonating. 

of  a  charge  in  another  autoclave.  Water  is  added  and  the 
solution  of  sodium  salicylate  pumped  out,  filtered,  and 
transferred  to  a  wooden  vat  with  stirrer.  The  salicylic  acid 
is  precipitated  by  addition  of  acid,  centrifuged  off  and  dried. 
The  crude  acid,  which  is  light  brown  in  colour,  is  purified  by 
distillation,  either  with  superheated  steam  (Ber.  (1875),  8,  537) 
or  with  air.  In  the  latter  case  the  acid  is  heated  in  a  shallow 
still  provided  with  a  stirrer,  or  in  shallow  trays,  to  a  tempera- 
ture of  about  I40°-i5o°.  A  current  of  air,  preheated  to  the 
same  degree,  is  blown  through  and  over  the  stirred  mass 
and  thence  into  a  suitable  condensing  chamber,  in  which 
provision  is  made  for  removing  the  heat ;  also  for  filtering 


ANTIPYRETICS  AND  ANALGESICS         137 


138         ORGANIC  MEDICINAL  CHEMICALS 

out  the  last  portions  of  salicylic  acid  flakes  from  the  air 
(see  D.  R.  PP.  10167,  29939,  38742).  A  ball  mill  designed 
for  the  production  of  dry  sodium  phenate  is  described  in 
E.  P.  105614/1916,  and  its  use  in  B.  P.  105611/1916.  Five 
per  cent,  of  sodium  sulphite  is  added  to  the  sodium  phenate 
solution  and  the  temperature  of  drying  is  given  as  250°-28o°. 
The  product  is  cooled  in  vacuo.  (See  also  E.  P.  105612/1916 
for  the  manufacture  of  salicylic  acid.)  In  B.  P.  105613/1916 
is  described  a  method  for  the  purification  of  the  crude  sodium 
salicylate  solution  (i  in  9),  whereby  it  is  first  pumped  through 
a  column  containing  granulated  zinc,  and  then,  at  a  temper- 
ature of  8o°-ioo°,  passed  through  a  tower  containing  a 
mixture  of  5  %  of  zinc  and  95  %  of  decolourising  charcoal. 
The  liquor  passing  from  the  tower  is  stated  to  yield,  on 
acidification,  pure  white  salicylic  acid.  According  to 
B.  P.  274/1901,  D.  R.  P.  133500,  sodium  phenate  may  be 
replaced  by  the  product  of  the  fusion  of  sodium  benzene 
sulphonate  (200  kgs.)  with  sodium  hydroxide  (in  kgs.). 

Salicylic  acid  is  sold  in  the  form  of  colourless,  light, 
matted  needles,  or  somewhat  heavier  prismatic  crystals. 
M.p.  157°. 

It  dissolves  in  500  parts  of  water  at  20°  ;  in  12  parts 
at  100°.  Soluble  in  3  J  parts  of  90  %  alcohol ;  in  55  parts 
of  chloroform  and  in  2  parts  of  ether. 

A  filtered  sample  of  the  aqueous  solution,  when  evaporated 
to  dryness,  should  afford  a  perfectly  white  residue.  One 
part  of  the  acid  should  dissolve  without  colouration  in  6 
parts  of  pure  sulphuric  acid.  If  i  gram  be  dissolved  in  20  c.c. 
of  cold  10  %  sodium  carbonate  solution,  the  liquid  shaken 
with  ether,  and  the  ether  be  allowed  to  evaporate  sponta- 
neously, the  residue,  if  any,  should  be  free  from  the  odour  of 
phenol.  An  alcoholic  solution  of  salicylic  acid  (10  %)  should 
be  unaffected  by  the  addition  of  silver  nitrate  solution,  after 
the  addition  of  a  few  drops  of  nitric  acid,  indicating  the 
absence  of  chlorides.  Salicylic  acid  is  both  antiseptic  and 
antipyretic.  It  is  a  specific  in  acute  rheumatism,  is  used  as 
a  lotion  in  pruritis  and  some  forms  of  eczema,  and  as  an 
injection  in  the  dysenteric  diarrhoea  of  children.  It  is  a 


ANTIPYRETICS  AND  ANALGESICS         139 

constituent  of  dusting  powders  and,  dissolved  in  collodion,  is 
employed  as  a  solvent  for  corns  and  warts. 

Of  the  salts  of  salicylic  acid  that  are  used  in  medicine, 
the  action  of  which  is  dependent  on  the  salicylic  radicle 
alone,  the  sodium  salt  only  needs  attention. 

Sodium  Salicylate  C6H4\coONa  160.— When  pre- 
paring sodium  salicylate  it  is  necessary  to  ensure  that  the 
materials  are  perfectly  pure  and  free  from  even  traces  of 
metals  such  as  iron,  and  to  work  in  porcelain,  nickel,  silver, 
or  glass-enamelled  apparatus.  16-5  parts  of  pure  sali- 
cylic acid  and  10  parts  of  pure  sodium  bicarbonate,  both 
free  from  iron,  are  intimately  mixed  in  a  porcelain  edge 
runner,  with  a  little  water,  to  a  thick  paste.  It  is  advis- 
able to  grind  the  acid  with  the  water  and  to  add  the 
bicarbonate  in  portions,  in  order  to  prevent  undue  frothing. 
After  most  of  the  carbon  dioxide  has  been  evolved  the  mixture 
is  evaporated  to  dryness  in  vacuo,  at  a  temperature  not 
exceeding  50°-6o°.  The  dried  sodium  salicylate  is  powdered 
and  sifted,  or,  if  flaky  crystals  are  required,  is  recrystallised 
from  hot  alcohol,  with  the  addition  of  some  ether.  A  slight 
excess  of  salicylic  acid  should  always  be  employed,  as 
alkaline  solutions  acquire  a  brown  colour  on  evaporation. 

The  sodium  salicylate  of  pharmacy  is  met  with  in  the 
form  of  white,  lustrous,  pearly  scales,  or  as  a  white  amorphous 
powder.  It  dissolves  in  i  part  of  water,  in  5  parts  of  90  % 
alcohol,  and  in  30  parts  of  absolute  alcohol.  The  aqueous 
(10  %)  solution  is  neutral  or  faintly  acid  to  litmus,  and 
should  be  perfectly  bright.  The  salt  should  dissolve  without 
effervescence  and  without  colouration  in  pure  sulphuric  acid. 
An  aqueous  solution  (10  %)  should  not  be  affected  by 
hydrogen  sulphide  solution  and  should  not  give  the  reactions 
for  chloride,  sulphate,  or  sulphite.  Sodium  salicylate  is 
less  irritating  than  salicylic  acid,  whilst  its  greater  solubility 
is  often  advantageous.  It  is  prescribed  in  acute  rheumatism, 
for  which  it  is  specific,  and  is  useful  in  influenza,  diabetes, 
sciatica,  and  acute  tonsilitis.  It  is  used  as  an  antipyretic 
in  pneumonia,  typhoid  fever,  and  all  pyrexial  affections.  It 


140         ORGANIC  MEDICINAL  CHEMICALS 

is  also  an  effective  antiseptic  for  fermentative  dyspepsia, 
and  increases  the  acidity  of  the  urine. 

Methyl  salicylate  C6H4\£OOCH      J 52. —Methyl  sali- 

cylate  is  the  main  constituent  of  the  oil  of  Gaultheria  pro- 
cumbens  (Wintergreen),  of  which  it  comprises  about  99  %. 
The  volatile  oil  of  Betula  lento,  (sweet  birch)  contains  99^8  % 
of  methyl  salicylate. 

It  is  prepared  synthetically  by  esterifying  salicylic  acid 
with  methyl  alcohol. 

According  to  Ullmann  (Enzyclopad.  der  Tech.  Chem.), 
2  parts  of  salicylic  acid,  2  parts  of  methyl  alcohol,  and  I  part 
of  concentrated  sulphuric  acid  are  boiled  together,  the 
esterification  mixture  being  worked  up  in  the  usual  way  by 
distillation. 

Methyl  salicylate  boils  at  2i9°-22i°,  and  has  a  specific 
gravity  of  1*185  to  1-90  at  15 -5°.  It  is  readily  soluble  in 
alcohol,  ether,  and  chloroform.  Very  slightly  soluble  in 
water. 

It  is  administered  internally,  in  acute  rheumatism  and 
sciatica.  It  is  employed  as  a  liniment  or  ointment  for 
external  application  to  the  joints  and  limbs.  It  is  a  good 
antiseptic  and  a  frequent  constituent  of  dentifrices. 

Methyl  salicylate  is  stated  to  be  better  for  external 
application  than  oil  of  wintergreen,  as  it  does  not,  like  the 
latter,  produce  an  eruption. 

ACETYLSALICYLIC  ACID  (Aspirin)  C6H4<^COOH   3  £(    l8°- 

— No  trustworthy  method  for  the  preparation  of  aspirin 
appears  yet  to  have  been  published. 

It  was  first  obtained,  in  a  very  impure  state,  as  indicated 
by  the  low  melting  point  (118°),  by  Kraut  (Ann.  150,  9), 
by  the  action  of  acetyl  chloride  upon  salicylic  acid  and  on 
sodium  salicylate. 

Bayer  applied  for  a  patent,  No.  10563  and  10581  of  1898, 
but  acceptance  of  this  was  declined,  no  doubt  on  account  of  the 
previous  publication  referred  to.  In  this  patent  application 
salicylic  acid  and  acetic  anhydride  were  caused  to  interact 


ANTIPYRETICS  AND  ANALGESICS  141 

at  temperatures  below  160°,  and  it  was  stated  that  acetyl 
chloride  could  be  employed  in  place  of  the  anhydride. 
According  to  a  method  given  by  Ullmann  (Enzyclopced.  der 
Tech.  Chem.),  138  kgs.  of  salicylic  acid  are  dissolved  in 
1 20  kgs.  of  acetic  anhydride,  and  500  grams  of  concentrated 
sulphuric  acid  added.  The  mixture  is  heated  at  5o°-6o°, 
and  the  temperature  taken  up  gradually  to  90°.  The  mass 
is  stirred  whilst  being  allowed  to  cool  and,  when  cold,  the 
acetylsalicylic  acid  is  filtered  off,  and  washed,  first  with  ice 
water  and  then  with  toluol.  The  acetic  acid  and  unused 
acetic  anhydride  are  distilled  off  from  the  mother  liquors  and 
salicylic  acid  recovered  from  the  residue. 

The  work  of  Tsakalotos  and  Horsch  (Bull.  Soc.  Chim. 
[IV]  17,  186  (1915))  serves  to  indicate  the  conditions  under 
which  the  acetylation  can  best  be  carried  out.  Studying  the 
velocity  of  the  formation  of  acetylsalicylic  acid  by  the  action 
of  acetic  anhydride  on  salicylic  acid  in  benzene  solution  these 
workers  found  the  reaction  to  be  one  of  the  second  order,  the 
velocity  being  multipliable  by  2 '2  for  each  rise  of  10°.  The 
temperatures  at  which  observations  were  made  were  25°,  30° 
and  50°.  At  90°  it  was  found  that  a  secondary  change 
occurred,  at  an  appreciable  velocity,  whereby  the  aspirin 
was  converted  into  salicylosalicylic  acid,  with  liberation 
of  acetic  anhydride,  an  irreversible  reaction. 

/OCOCH,  XC6H4COOH 

XCOOH  \COC6H4OH + (CH3C°)  20 

Using  equimolecular  quantities  of  the  reacting  materials 
in  a  dilute  benzene  solution  (ca.  i  %)  at  25°,  equilibrium 
was  reached  in  24  hours,  when,  calculated  from  the  titrations 
given,  94  %  of  the  theoretical  amount  of  acetylsalicylic 
acid  had  been  produced  under  the  conditions  referred  to, 
while  at  50°  in  3  J  hours  only  86  %  of  conversion  had  taken 
place.  In  order  to  obtain  complete  conversion  an  excess  of 
acetic  anhydride  is  required  and  the  temperature  and  time 
of  reaction  must  be  adjusted  to  the  lowest  practical  limits. 
The  presence  of  iron  salts  must  be  rigidly  excluded,  as  this 
not  only  produces  colour  by  interaction  with  salicylic  acid, 


142         ORGANIC  MEDICINAL  CHEMICALS 

but  brings  about  catalytically  the  production  of  compounds 
in  which  the  aceto  group  COCH3  has  entered  the  nucleus. 

The  aspirin  is  filtered  from  the  acetylation  mixture, 
dried,  and  recrystallised  from  dilute  alcohol  or  other  solvent. 

Acetylation  with  Acetyl  Chloride. — The  acetylation  of 
salicylic  acid  may  also  be  carried  out  with  acetyl  chloride  ; 
it  is  a  matter  for  careful  determination  according  to  price 
whether  this  reagent  or  acetic  anhydride  is  the  more 
economical  to  use.  The  employment  of  the  chloride  is 
dominated  by  similar  considerations  to  those  discussed  in 
connection  with  the  anhydride.  Contamination  by  metals 
such  as  iron  or  aluminium  must  be  rigorously  excluded, 
lest  Friedel-Kraft's  condensation  be  induced,  and  the  working 
temperature  must  be  kept  as  low  as  is  practicable.  Further, 
it  is  necessary  to  use  a  relatively  large  excess  of  the  acetylat- 
ing  agent,  as  the  reaction — 

CH3COC1+C6H4OH-COOH  ^  C6H4OCOCH3-COOH  +HC1 

is  reversible. 

The  reaction  is  carried  out  in  a  good  enamelled,  tiled,  or 
earthenware-lined,  jacketed  still  provided  with  a  manhole 
for  charging,  a  thermometer,  a  glass  or  earthenware  pipe 
through  which  the  acetyl  chloride  is  introduced,  with  an 
earthenware  or  lead  condenser,  a  receiver  for  the  distillate 
(acetyl  chloride),  and  a  scrubber  containing  a  solvent,  such 
as  acetic  acid  or  high  boiling  petrol,  for  freeing  the  hydrogen 
chloride  vapours  as  far  as  possible  from  acetyl  chloride 
before  being  passed  into  an  absorption  tower. 

The  still  is  charged  with  138  parts  (i  mol.)  of  salicylic 
acid,  to  which  are  added  50  parts  of  glacial  acetic  acid  and 
200  parts  of  acetyl  chloride  (ca.  2\  mols.).  The  still  is 
heated  up  gently,  steam  being  shut  off  as  soon  as  the  reac- 
tion is  seen  to  be  proceeding  vigorously.  Much  HC1  is 
evolved,  and  acetyl  chloride  commences  to  pass  slowly 
over.  As  soon  as  a  slackening  is  noticed  the  steam  is  applied 
again,  the  temperature  being  raised  gradually  to  60°. 
When  the  reaction  has  nearly  ceased,  the  temperature  is 
raised  slowly  to  70°  in  order  to  free  the  reaction  mixture 


ANTIPYRETICS  AND  ANALGESICS  143 

as  far  as  possible  from  acetyl  chloride.  The  application  of 
a  slight  vacuum  towards  the  finish  greatly  facilitates  this. 
When  distillation  has  ceased,  the  still  content  is  blown  out 
into  enamelled  pans  and  left  until  crystallisation  is  complete. 
The  crystallised  mass  is  then  centrifuged,  washed  with  a 
small  quantity  of  solvent,  and  dried  at  3o°-40°  until  practi- 
cally free  from  volatile  acid. 

Crystallisation  of  Aspirin. — A  wide  choice  of  solvents 
for  the  purification  of  aspirin  can  be  exercised  according  to 
the  circumstances.  Benzene,  ethyl  or  methyl  acetate, 
chloroform,  ethyl  or  methyl  alcohol,  may  each  be  employed. 
It  is  important  that  high  temperature  should  be  avoided, 
in  order  to  prevent  the  production  of  salicylosalicylic  acid, 
which  affects  the  product  detrimentally.  (Bull.  Soc.  Chem. 
(1918)  (IV.)  23,  16.) 

Tsakalotos  and  Horsch  (ibid.  (1914),  15,  743)  have  shown 
that  cold  water,  in  which  aspirin  is  soluble  only  to  the  extent 
of  I  in  400,  exerts  an  extremely  slight  hydrolysing  action, 
which,  however,  is  enormously  increased  by  the  presence  of 
mineral  acids,  and  to  some  extent  by  acetic  acid. 

A  useful  method  of  crystallisation  is  to  dissolve  the  acid, 
which  must  be  quite  free  from  mineral  acid,  and  as  free  as 
possible  from  acetic  acid,  in  methyl  or  ethyl  alcohol  at  a 
moderate  temperature  and  to  throw  it  out  of  solution  by  the 
addition  of  cold  water. 

Acetylsalicylic  acid  crystallises,  when  quite  pure,  in 
small  symmetrical  rhombic  plates ;  though  it  is  more 
frequently  met  with  in  the  form  of  more  or  less  irregularly 
shaped  needles.  Much  discussion  has  taken  place  regarding 
the  melting  point  of  pure  aspirin.  This  can  be  made  to 
vary  considerably,  by  altering  the  rate  of  heating  ;  but 
under  the  conditions  prescribed  by  the  British  Pharma- 
copoeia it  may  be  taken  as  I34°-I35°.  It  dissolves  in  400 
parts  of  cold  water,  and  in  5  parts  of  90  %  alcohol. 
O'l  gram  treated  with  5  c.c.  of  alcohol  and  diluted  with 
20  c.c.  of  water  should  not  be  coloured  violet  on  the  addition 
of  i  drop  of  ferric  chloride  solution  (absence  of  salicylic 
acid).  Volatile  (acetic)  acid  should  be  absent  as  indicated 


144         ORGANIC  MEDICINAL   CHEMICALS 

by  a  strip  .of  moistened  blue  litmus  paper,  suspended  in  a 
closed  bottle  above  a  sample  of  the  powdered  substance,  not 
becoming  reddened  within  20  minutes. 

Acetylsalicylic  acid  is  now  probably  the  most  generally 
used  analgesic  and  antipyretic.  Its  action  is  similar  to  that 
of  salicylic  acid  and  the  salicylates,  and  it  does  not  irritate  the 
stomach,  to  a  large  extent  passing  through  it  undecomposed. 
It  is  absorbed  from  the  duodenum,  where  it  is  slowly  hydro- 
tysed,  and  it  is  said  to  be  due  to  its  gradual  absorption  in  this 
way  that  it  does  not  exhibit  the  cumulative  toxic  action  of 
salicylic  acid. 

Calcium  acetylsalicylate 
XOCOCH3 


.     434- 

The  preparation  of  this  compound  is  attended  with  some 
difficulty  on  account  of  the  readiness  with  which  it  hydrolyses 
and  the  consequent  necessity  for  avoiding  heat  as  well  as 
that  of  preventing  contamination  by  iron. 

The  following  methods  of  procedure  have  been  protected 
by  patents  :— 

(a)  Calcium  acetate,  80  parts,  dissolved  in  240  parts  of 
cold  water,  is  added  to  a  cold  solution  of  180  parts  of  acetyl- 
salicylic  acid  in  1500  parts  of  methyl  alcohol.     Calcium 
acetylsalicylate   crystallises  out  and  is  filtered  off,  washed 
with  methyl  alcohol,  and  dried.    (K.  P.  4053/1912.   D.  R.  PP. 
253924,  255673.) 

(b)  Acetylsalicylic  acid,  i  kg.,  is  rubbed  up  with  2  kgs. 
of  water,  and  350  grams  of  precipitated,  iron-free,  calcium 
carbonate  added,  with  stirring.     When  evolution  of  CO2  is 
at  an  end,  the  solution  is  filtered  as  quickly  as  possible  and 
mixed  with  3  to  4  volumes  of  methyl  alcohol.     The  calcium 
salt  crystallises  out,  and  is  filtered,  washed  with  methyl 
alcohol,  and  dried  at  a  low  temperature.     (D.  R.  P.  251333.) 

(c)  Acetylsalicylic    acid,     180    parts,    and     anhydrous 
calcium  chloride,  56  parts,  are  dissolved  in  2000  parts  of 
anhydrous  methyl  alcohol.     A  solution  of  17  parts  of  NH3 
in  methyl  alcohol  is  added,  whereupon  the  calcium  acetyl- 
salicylate crystallises  out.     (D.  R.  P.  275038.) 


ANTIPYRETICS  AND  ANALGESICS         145 

(d)  Equivalent  quantities  of  acetylsalicylic  acid  and  dry 
sifted  hydrated  lime,  Ca(OH)2,  are  intimately  mixed.  The 
mixture  is  moistened  with  a  small  amount  of  a  suitable 
solvent,  and  the  whole  triturated  until  a  dried  sample  of 
the  solid  is  found  to  be  completely  soluble  in  water.  The 
solvent  is  then  removed  by  filtration,  and  the  calcium 
acetylsalicylate  dried,  powdered,  and,  if  necessary,  ex- 
tracted with  small  quantities  of  dry  ether  until  neutral, 
after  which  it  is  dried  again.  Suitable  solvents  are  stated 
to  be  methyl  alcohol,  methylethyl  ketone,  methyl  or  ethyl 
acetate,  methyl  or  ethyl  formate,  amyl  acetate,  and  ethyl 
alcohol.  (E.  P.  100343/1916  ;  D.  R.  PP.  27668,  286691, 
287661.) 

Calcium  acetylsalicylate  is  a  white  crystalline  powder, 
which  dissolves  in  6  parts  of  water.  It  should  be  neutral 
in  reaction  to  litmus,  and  practically  free  from  salicylic  acid. 

It  is  employed  in  the  treatment  of  rheumatism,  of 
influenza,  of  catarrhs,  and  neuralgia,  and  generally  as  an 
analgesic.  It  is  stated  also  to  be  efficacious  in  cases  of 
obstinate  diarrhoea. 

Sodium  acetylsalicylate  (D.  R.  P.  270326). — 180  parts 
of  finely  powdered  acetylsalicylic  acid  are  mixed  intimately 
with  55  parts  of  powdered  anhydrous  sodium  carbonate  and 
150  parts  of  ethyl  acetate.  The  mixture  is  ground  in  a  mill 
for  some  hours,  until  a  test  portion  dissolves  completely  in 
water,  without  evolution  of  CO2.  The  product  is  then 
filtered  off,  washed  with  ether,  and  dried  in  vacuo. 

The  lithium  salt  may  be  similarly  prepared.  It  has  been 
specially  recommended  for  treatment  of  rheumatism. 


10 


SECTION  V.—  OKGANIC  ANTISEPTICS  AND 
DISINFECTANTS 

A  VERY  large  variety  of  substances  (antiseptics)  possess 
the  property  of  inhibiting  the  growth  of  bacteria,  and  many 
of  these  possess  also  the  property  of  killing  them  (disin- 
fectants). There  are  numerous  inorganic  substances  not 
coming  within  the  scope  of  this  volume  which  act  powerfully 
in  these  respects.  Such,  for  instance,  are  boric  acid,  hydrogen 
peroxide,  mercury,  zinc,  bismuth  and  silver  salts,  the 
hypochlorites  and  the  free  halogens.  Others  to  be  classed 
among  the  organic  substances  with  which  we  are  concerned 
are  dealt  with  in  different  sections  of  this  book ;  such  are 
exemplified  by  quinine,  benzoic  and  salicylic  acids,  ether 
and  chloroform,  etc. 

Disease  germs  may  need  to  be  attacked  by  a  disinfectant  in 
widely  different  circumstances  ;  they  may  be  on  a  superficial 
wound,  a  diseased  skin  lesion,  a  mucous  surface,  or  in  the 
intestines,  veins  or  tissues,  and  the  agent  suitable  in  one 
of  these  cases  is  not  necessarily  suitable  in  the  others. 

Simple  estimates  of  germicidal  action  made  in  vitro 
have  proved  misleading  as  to  the  practical  value  of  the  agent. 
In  testing  antiseptics  it  is  necessary  to  choose  methods 
which  are  in  conformity  with  the  purpose  for  which  they 
are  to  be  used  as  regards  considerations  of  concentration, 
temperature,  and  above  all  of  the  medium.  Dakin  has 
shown  that  in  a  medium  composed  of  a  mixture  of  blood 
serum  and  muscle  extract  very  different  results  are  obtained 
from  those  in  which  water  is  employed. 

In  a  mixture  of  blood  serum  and  muscle  extract  hydrogen 
peroxide  possesses  negligible  value  as  a  disinfectant, 

146 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  147 

while  the  activity  of  sodium  hypochlorite  in  this  medium 
is  much  greater  than  in  defibrinated  blood.  He  has  also 
pointed  out  that  a  likely  explanation  of  the  deep-seated 
action  of  chlorine  antiseptics  is  due  to  the  formation  of 
chloramine  groupings  in  the  amino-acid  residue  of  the 
proteins. 

The  cells  of  a  body  surface  may  become  poisoned  by  a 
particular  disinfectant,  so  that  healing  is  retarded,  or  again 
the  curative  action  of  the  blood  may  be  weakened  by  damage 
to  the  leucocytes  by  the  disinfectant.  (Recent  experi-  X 
mentation  has  been  largely  directed  to  the  discovery  of 
substances  which  differentiate  between  the  protoplasm  of 
the  host  and  that  of  its  invading  microbej  forms  of  proto- 
plasm differ  in  their  affinities  for  dyes,  and  dyes  have 
already  been  discovered  which  exert  powerful  germicidal 
action,  as  instanced  by  the  flavine  antiseptics^)  There  is, 
therefore,  reason  to  hope  that  great  improvements  upon  the 
older  methods  of  disinfection  are  at  hand.  In  the  present 
section  various  phenolic  antiseptics  are  classed  together, 
as  are  also  the  halogen  disinfectants.  Other  than  this,  but 
little  chemical  classification  of  these  substances  is  possible. 

PHENOL  (carbolic  acid)  C6H5OH.  94.— Phenol  is 
manufactured  technically  by  fusing  benzene-monosulphonic 
acid  with  caustic  soda.  Another  method,  however,  has 
been  protected  (B.  P.  25555/1912),  whereby  monochloro- 
benzene  is  heated  under  a  pressure  of  200-300  atmospheres, 
at  300°,  with  4  molecular  proportions  of  15  to  20  %  caustic 
soda.  A  96  %  yield  of  pure  phenol  is  obtained. 

Preparation  of  Benzene sulphonic  acid  (see  Cain,  Manu- 
facture of  Intermediate  Products  for  Dyes,  p.  101). — The 
sulphonation  of  benzene  is  performed  in  a  closed,  cast- 
iron,  steam-jacketed  vessel,  fitted  with  a  helical  stirrer 
having  a  speed  of  180  revolutions  per  minute  (Grandmougin, 
Rev.  Prod.  Chim.  (1916),  19, 373).  The  lid  is  supplied  with  a 
thermometer  pipe,  a  reflux  condenser,  and  a  charging  hole. 
The  vessel  is  fitted  with  a  valve  at  the  bottom  for  running 
out  the  finished  batch.  It  is  charged  with  225  kilos  of 
sulphuric  acid  (100  %)  and  100  kilos  of  benzene.  The 


148         ORGANIC  MEDICINAL  CHEMICALS 

stirrer  must  be  kept  running  constantly.  The  temperature 
rises  to  6o°-7O°  and  is  then  raised  further  by  turning  steam 
into  the  jacket  so  as  to  keep  the  benzene  gently  boiling. 
At  the  end  of  seven  to  eight  hours  the  benzene  should  have 
disappeared  and  the  product  should  be  completely  soluble 
in  water. 

Alternatively,  the  vessel  may  be  charged  with  260  kilos 
of  98  %  acid  and  40  kilos  of  benzene.  The  remaining 
60  kilos  are  added  as  the  temperature  ceases  to  rise,  and 
finally  the  temperature  is  raised  to  80°. 

In  D.  R.  P.  113784,  100  parts  of  benzene  are  heated  with 
250  parts  of  an  acid  sodium  sulphate,  NaH3(SO4)2,  prepared 
by  treating  sodium  bisulphate  with  sulphuric  acid  (66°  Be.). 
The  reaction  mixture  is  diluted  with  water,  and  neutralised 
with  milk  of  lime,  and  filtered  from  gypsum,  the  filtrate 
constituting  a  solution  of  sodium  benzenesulphonate. 

Sodium  Benzenesulphonate. — The  mixture  obtained  as 
above  by  the  sulphonation  of  100  kilos  of  benzene  is  run 
into  300  litres  of  water  contained  in  a  lead -lined  vat  fitted 
with  a  stirrer  and  a  perforated-lead  steam-coil,  and  nearly 
neutralised  with  milk  of  lime  (about  140  kilos  of  lime  and 
700  litres  of  water).  Complete  neutralisation  is  effected  by 
adding  precipitated  calcium  carbonate  obtained  from  the 
next  operation.  The  whole  is  heated  to  boiling,  about 
450  litres  of  cold  water  are  added  so  as  to  render  the  calcium 
sulphate  easily  filterable,  and  it  is  filtered  through  a  filter 
press  at  about  60°.  The  calcium  sulphate  is  well  washed,  the 
wash  liquors  being  used  to  dilute  the  next  sulphonation 
mixture  or  to  slake  the  lime.  The  filtrate,  which  contains 
calcium  benzenesulphonate,  is  stirred  and  sodium  carbonate 
added  until  a  filtered  sample  gives  no  further  precipitate 
with  the  alkali ;  about  70  kilos  of  sodium  carbonate  are 
required.  The  precipitated  calcium  carbonate  is  allowed 
to  settle,  the  clear  liquid  separated  by  decantation  or 
filtration,  evaporated  and  finally  dried.  Drum  dryers  are 
used  in  America  for  this  purpose.  About  230-235  kilos  of 
sodium  benzenesulphonate  are  obtained  from  100  kilos  of 
benzene.  Instead  of  sodium  carbonate  the  sulphate  may 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  149 

be  used  in  the  above  operation,  and,  further,  the  correct 
amounts  of  lime  and  sodium  sulphate  may  be  added  to  the 
diluted  sulphonation  mixture  (U.  S.  P.  1207798). 

As  an  alternative  method  the  sulphonation  mixture 
from  100  kilos  of  benzene  is  poured  into  a  lead-lined  tank 
(25  cm.  deep)  fitted  with  an  agitator,  and  containing  about  250 
litres  of  water  and  150  kilos  of  anhydrous  sodium  sulphate. 
On  cooling,  the  sodium  benzenesulphonate  is  centrifuged 
or  filtered.  The  separation  is  rather  slow  and  it  is  necessary 
to  have  a  large  surface  for  this  purpose.  About  180  square 
metres  are  required  for  i  ton  of  benzene.  The  product 
contains  about  84  %  of  the  sodium  salt  and  the  yield  is 
about  210-220  kilos,  but  can  be  increased  with  good 
working.  The  filtrate  from  the  separation  may  be  used 
(U.  S.  P.  1179415)  to  acidify  the  sodium  phenoxide  from  the 
fusion.  Sodium  carbonate  may  be  used  instead  of  the 
sulphate  ;  in  U.  S.  P.  1191880  the  phenol  from  the  sodium 
phenoxide  is  liberated  by  means  of  carbon  dioxide  and  the 
sodium  carbonate  so  formed  employed  to  neutralise  the 
sulphonation  mixture. 

Fusion  with  Sodium  hydroxide. — This  is  done  in  an  open 
cast-iron  pan  fitted  with  an  agitator  and  heated  by  gas. 
lyocal  overheating  must  be  avoided,  as  this  gives  rise  to 
the  formation  of  thiophenol.  Two  hundred  and  twenty 
kilos  of  sodium  hydroxide  (90  %  NaOH)  are  placed  in  the 
pan,  20  litres  of  water  added,  and  the  mixture  is  heated  to 
290°.  Two  hundred  and  eighty  kilos  of  sodium  benzene 
sulphonate  are  slowly  added,  care  being  taken  that  the 
temperature  does  not  drop  but  rises  gradually  to  300°. 
When  the  addition  is  finished,  the  temperature  may  be 
raised  to  3i5°-33O°,  but  must  not  go  beyond  340°.  The 
reaction  proceeds  fairly  rapidly  and  the  mass  finally  becomes 
fluid  and  homogeneous.  The  fusion  takes  3-4  hours  as  a 
rule.  It  is  now  run,  while  still  fluid,  into  cold  water, 
three  parts  of  the  latter  being  used  for  one  part  of  sodium 
hydroxide  employed.  The  temperature  of  the  water  rises 
to  nearly  100°,  and  the  solution  has  a  density  of  27°  Be. 
The  sodium  phenoxide  is  thus  dissolved  whilst  most  of  the 


i5o         ORGANIC  MEDICINAL  CHEMICALS 

sodium  sulphite  separates  in  the  anhydrous  condition.  The 
whole  is  filtered  and  the  sulphite  is  mixed  with  water  at  85° 
and  filtered  again,  the  wash  waters  being  added  to  the 
solution  phenoxide.  This  solution  is  treated  with  sulphuric 
acid  (about  190  kilos  of  50°  Be.)  until  it  is  neutral  to  litmus, 
and  after  a  few  hours  the  phenol,  which  forms  as  a  yellowish 
oily  layer  on  the  top  of  the  aqueous  solution,  is  separated. 
By  allowing  the  aqueous  solution  to  crystallise,  sodium 
sulphate  is  obtained,  which  can  be  again  used  in  the 
process. 

The  phenol  is  washed  with  water  and  distilled  in.  a  vacuum. 
A  silver  or  silver-plated  copper  coil  may  be  used. 

The  yield  by  the  " salting  out"  method  is  82-83  %. 
By  the  liming  method  85  %  can  be  obtained. 

Phenol,  or  carbolic  acid,  forms  small,  colourless, 
deliquescent  crystals,  which  have  a  tendency  to  acquire  a 
pink  tinge  on  exposure  to  air  and  light ;  whilst  synthetic 
phenol  turns  yellow  to  brown.  It  is  soluble  in  12  to  13 
parts  of  water,  and  is  very  readily  soluble  in  alcohol, 
ether,  and  other  organic  solvents. 

The  melting  point  should  be  not  less  than  38 -8°  (102°  F.); 
synthetic  phenol  usually  fusing  at  40-5°.  B.p.  i78°-i82°. 

Ten  parts  liquefied  by  the  addition  of  i  part  of 
water  should  form  a  clear  liquid  with  3  to  4  parts 
of  water,  and  be  completely  dissolved  by  120  parts 
of  water. 

One  volume  of  phenol  liquefied  by  the  addition  of  10  % 
of  water  should  form  a  clear  liquid  when  mixed  with  i  vol. 
of  glycerine,  and  not  be  rendered  turbid  when  3  vols.  of 
water  are  added  (freedom  from  cresylic  acid). 

Phenol  acts  as  an  antiseptic,  a  disinfectant,  and  a  local 
anaesthetic.  Externally,  when  undiluted,  it  is  powerfully 
caustic ;  as  a  lotion  it  is  applied  for  eczema,  ulcers, 
carbuncles,  ringworm  and  other  parasitic  skin  diseases.  It 
is  given  internally  as  an  intestinal  and  gastric  antiseptic, 
in  phthisis,  bronchitis,  whooping-cough,  and  as  a  prophy- 
lactic in  scarlet  fever.  A  solution  of  sodium  phenate  is 
used  as  an  antiseptic  mouth-wash. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  151 

OH 

SALOL  (phenylsalicylate)  <^>COOC6H5.  214.—  Accord- 
ing to  D.  R.  P.  38973,  salol  is  prepared  by  the  action  of 
phenol  and  phosphorus  oxychloride  upon  salicylic  acid  or 
sodium  salicylate, 


320  188         153 

+NaP03+NaCl+2HCl 


428 
or  by  using  sodium  phenate  in  place  of  phenol, 


428 

By  an  addition  to  the  above  patent,  D.  R.  P.  43713,  benzol 
or  toluol  may  be  used  as  a  diluent  or  vehicle  in  the 
above  reactions,  sodium  or  potassium  acid  sulphate  being 
employed  as  dehydrating  agent.  When  employing  salicylic 
acid,  phenol,  and  POC13,  these  substances  are  mixed  in  the 
proportions  required  by  the  equation  and  the  mixture  is 
heated,  in  an  enamelled  still  (Fig.  21),  at  i20°-i3O°  for 
2  hours.  The  vessel  is  provided  with  a  reflux  condenser, 
and  provision  is  made  for  taking  away  the  HC1  fumes 
that  are  evolved.  After  the  reaction  mixture  has  cooled, 
the  upper  layer  is  separated  and  agitated  with  sodium 
carbonate  solution  until  free  from  salicylic  acid.  It  is  then 
washed  with  water,  dried  with  calcium  chloride,  distilled 
under  a  vacuum  of  10  mm.  and  obtained  pure  and  in  crystal- 
line form  by  crystallisation  from  60  %  alcohol. 

It  has  been  stated  that  it  is  preferable  to  use  sodium  salicy- 
late and  sodium  phenate  in  carrying  out  the  above  reaction, 
as  the  formation  of  phosphoric  esters  is  thereby  inhibited. 

By  another  process,  D.  R.  P.  31984,  phosgene  is  employed 
as  a  condensing  agent  in  place  of  phosphorus  oxychloride. 


152 


ORGANIC  MEDICINAL   CHEMICALS 


Fifty  kilos  of  sodium  phenate  and  80  kilos  of  sodium 
salicylate  (anhydrous)  are  mixed  in  a  cast-iron  vessel  provided 
with  stirring  gear  and  a  steam  jacket  or  internal  coils,  and 


FIG.  21. — Enamelled  still. 


phosgene  is  introduced.  Heat  is  developed,  a  vigorous 
reaction  taking  place.  It  is  completed  by  gentle  heating, 
after  which  the  salol  is  distilled  over  in  steam  and  recrystal- 
lised  from  dilute  alcohol. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  153 


116  160          99 


214 

Salol   forms   colourless   translucent   crystals,    possessing    a 
characteristic  odour.     M.p.  42°-43°. 

It  is  insoluble  in  cold  water  ;  dissolves  in  12  parts  of 
90  %  alcohol  ;  very  soluble  in  ether,  chloroform  and  most 
organic  solvents. 

When  shaken  with  50  times  its  weight  of  water  and 
filtered,  the  filtrate  should  not  afford  the  reactions  of  chlorides 
or  sulphates  ;  nor  give  a  violet  or  blue  colouration  on  treat- 
ment with  ferric  chloride  solution  (absence  of  phenol  and  of 
salicylic  acid)  . 

Salol  is  antipyretic  and  antiseptic  ;  it  is  used  largely  as 
an.  intestinal  and  urinary  disinfectant.  It  is  stated  to  pass 
unchanged  through  the  stomach,  but  to  be  decomposed  in 
the  small  intestine  into  its  components,  phenol  and  salicylic 
acid. 

Salol  has  been  recommended  in  dyspepsia,  intestinal 
fermentation,  intestinal  tuberculosis,  in  acute  and  chronic 
rheumatism,  and  in  cholera,  typhoid  fever,  and  smallpox. 
It  has  also  been  applied  externally  to  wounds  and  employed 
as  a  constituent  of  antiseptic  mouth-washes. 

OH 

RESORCINOL     (m-dihydroxy  -benzene)      f       H'     IIC)*  — 


Resorcinol  is  manufactured  by  fusing  benzene-w-disulphonic 
acid  with  caustic  soda.  The  following  description  is  given 
by  Miihlhauser  (Dingl.  Polyt.  J.  (1887),  263,  154),  and  is  taken 
from  Cain  (Manufacture  of  Intermediate  Products  for  Dyes, 
p.  127). 

Preparation  of  Benzenemonosulphonic  acid.  —  Three  hun- 
dred kilos  of  sulphuric  acid,  67°  Be.,  and  60  kilos  of  pure 
benzene  are  placed  in  a  cast-iron  jacketed  vessel  of  400 
litres  capacity  fitted  with  stirrer  and  a  lead  reflux  condenser, 


154         ORGANIC  MEDICINAL  CHEMICALS 

the  mixture  well  stirred  and  warmed  to  about  80°.  The 
pipe  between  the  reflux  condenser  and  the  vessel  should 
feel  only  slightly  warm  to  the  hand.  The  process  is  carried 
on  for  10  hours,  when  monosulphonation  should  be  complete. 

Preparation  of  Salt  of  Benzene-m-disulphonic  acid. — Next 
day  the  above  batch  is  blown  into  a  cast-iron  oil-jacketed 
vessel  of  800  litres  capacity,  fitted  with  a  stirrer  and  an  ordi- 
nary lead  condenser ;  85  kilos  of  dry  ground  sodium  sulphate 
are  added,  the  stirrer  is  kept  going,  and  the  oil  bath  heated 
to  240°.  After  about  4  hours  the  contents  of  the  vessel  will 
have  reached  the  temperature  of  about  225°  and  are  kept 
at  this  point  for  about  8  hours.  During  the  first  period  of 
heating  benzene  distils  over  and  sulphur  dioxide  is  evolved. 
On  the  following  day  the  contents  of  the  vessel  are  blown 
into  1500  litres  of  water  contained  in  a  vat  of  3000  litres 
capacity,  and  neutralised  with  sifted  slaked  lime  made 
from  200  kilos  of  quicklime.  In  order  to  render  the 
calcium  sulphate  easily  filterable  about  800  litres  of  cold 
water  are  added  to  the  boiling  mixture,  which  is  then  filtered 
through  a  filter  press.  The  press  cake  is  boiled  up  with 
about  1500  litres  of  water,  cold  water  being  added  as  before, 
and  again  filtered.  The  combined  filtrates  are  evaporated  to 
about  2000  litres  and  then  treated  in  a  vat  with  6  to  10  kilos 
of  sodium  carbonate,  to  convert  the  calcium  salt  into  the 
sodium  salt.  The  calcium  carbonate  is  filtered  off  by  means 
of  a  filter  press  and  the  filtrate  evaporated  in  two  evaporating 
pans,  1500  litres  capacity,  provided  with  stirrers,  until  it 
is  thick  enough  to  stop  the  stirrers.  The  moist  salt  is  then 
completely  dried  in  drying  pans,  being  continually  stirred 
with  an  iron  rake,  and  the  dry  powder  is  ground  and  sieved. 
Yield  200  kilos. 

Fusion. — Two  hundred  and  fifty  kilos  of  solid  caustic  soda 
are  put  into  a  cast-iron  vessel  (600  litres)  fitted  with  stirrer, 
and  heated  by  direct  fire  ;  10  kilos  of  water  are  added  and  the 
mixture  is  heated  until  no  skin  is  formed  on  the  surface  and 
the  crusts  forming  on  the  sides  have  also  melted  (270°).  The 
stirrer  is  started  and  125  kilos  of  the  dry  sodium  salt  are 
added  within  about  half  an  hour,  care  being  taken  that  the 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  155 

mass  does  not  froth  over.  This  can  be  regulated  by  stopping 
and  restarting  the  stirrer.  The  foaming  gradually  ceases 
and  the  melt  acquires  an  oily  appearance  ;  it  becomes 
yellow  and  then  brown.  When  no  further  reaction  appears 
to  be  taking  place  (8-9  hours),  the  mass  is  scooped  out  on  to 
iron  trays,  where  it  solidifies  on  cooling. 

Extraction. — The  broken-up  cakes  are  added  to  500  litres 
of  water  in  a  1500  litre  earthenware  vessel  and  made  just 
acid  with  hydrochloric  acid  (7  to  8  carboys).  When  the 
sulphur  dioxide  has  been  driven  off,  the  solution  is  blown  into 
an  extraction  apparatus  consisting  of  a  closed  vessel  (2000 
litres)  fitted  with  a  stirrer,  a  separator  (2000  litres),  and  a 
container  for  the  solvent  (500  litres).  It  is  extracted  four 
times  with  amyl  alcohol,  100  litres  being  used  for  each 
extraction.  The  solution  and  amyl  alcohol  are  mixed  together 
for  about  30  minutes  and  then  blown  into  the  separator, 
which  is  a  cylinder  with  a  pointed  end.  After  settling  for 
an  hour  the  aqueous  solution  is  run  back  into  the  extractor. 
The  solution  of  resorcinol  in  amyl  alcohol  is  first  heated  to 
about  100°  with  indirect  steam  and  then  steam  is  passed 
in  to  drive  over  the  solvent.  When  only  water  is  being 
condensed,  the  resorcinol  solution  is  run  into  an  enamelled 
drying  pan,  where  the  water  is  evaporated. 

Purification. — The  resorcinol  is  purified  by  distillation 
in  a  vacuum.  The  contents  of  the  drying  pan  are  transferred 
to  a  copper  still  (75  litres  capacity)  and  heated,  at  first  with- 
out vacuum  being  applied.  A  little  water  and  phenol  pass 
over  first.  At  about  190°  the  pressure  is  reduced  to  130 
mm.  and  the  resorcinol  distilled  over.  About  20-23  kilos 
of  pure  resorcinol  are  obtained  from  125  kilos  of  the  disul- 
phonate. 

Ether  may  be  used  in  place  of  amyl  alcohol  for  the 
extraction. 

Resorcinol  forms  white,  or  nearly  white,  glistening  needle- 
shaped  or  prismatic  crystals.  One  hundred  parts  of  water 
dissolve  86-4  parts  at  o°,  147  parts  at  12-5°,  and  228*6  parts 
at  30°.  It  is  very  readily  soluble  in  alcohol  and  in  ether. 
M.p.  ii8°-ii9°.  B.p.  276°. 


156         ORGANIC  MEDICINAL  CHEMICALS 

The  aqueous  solution  should  be  colourless  and  should 
yield  no  precipitate  when  treated  with  lead  acetate  (absence 
of  catechol).  No  odour  of  phenol  should  be  emitted  when 
the  concentrated  aqueous  solution  is  gently  heated.  The 
aqueous  solution  should  not  give  a  red  colour  with  a  pine 
splinter  nor  afford  an  odour  of  benzoquinone  when  warmed 
with  ferric  chloride  (absence  of  quinol) . 

Resorcinol  is  a  powerful  antiseptic.  It  is  employed  as 
a  spray  (i  to  2  %)  in  diphtheria  and  whooping-cough,  in 
ointments  (5  to  10  %)  in  the  treatment  of  skin  diseases,  and 
in  lotions  for  removing  dandruff  from  the  scalp.  Internally 
it  is  prescribed  in  diarrhoea  and  gastric  affections.  It 
exercises  a  very  depressant  action  on  the  heart. 

MONOACETYL-RESORCINOL  (Euresol)  C6H4<^OCOCH    152. 

— Ten  kilos  of  resorcinol  (D.  R.  P.  103857)  are  mixed  with 
2*2  litres  of  acetic  anhydride  and  1*8  litres  of  glacial  acetic 
acid,  and  heated  for  ij  hours  at  40°,  followed  by  an  hour's 
heating  at  45°.  Excess  of  acetic  anhydride  is  then  destroyed 
by  careful  addition  of  water,  and  the  acetic  acid  removed 
completely  by  distillation  in  vacuo  and  with  the  aid  of  a 
current  of  carbon  dioxide.  Pure  resorcinol  monoacetate 
remains.  It  is  completely  soluble  in  caustic  alkali  and 
distils  at  283°. 

Alternatively,  5  kilos  of  resorcinol  dissolved  in  7-5  litres 
of  glacial  acetic  acid  are  treated  with  3-5  litres  of  acetyl 
chloride,  with  good  cooling.  The  mixture  is  finally  warmed 
for  an  hour  at  40°  and  worked  up  as  in  the  previous  example. 

According  to  D.  R.  P.  281099,  8  parts  of  resorcinol  are 
mixed  with  7^  parts  of  acetic  anhydride  and  2  parts  of  glacial 
acetic  acid  and  the  mixture  heated  on  the  water  bath  for 
several  hours.  Acetic  acid  is  then  distilled  off  in  a  vacuum, 
and  a  current  of  slightly  superheated  steam  is  passed,  in 
vacuo,  over  the  residue,  which  is  heated  at  100°,  until  it  is 
free  from  any  unpleasant  smell. 

Euresol  is  a  thick,  honey-like,  yellow  liquid,  which  is 
fairly  soluble  in  water,  and  readily  soluble  in  acetone.  It 
should  possess  a  saponification  value  agreeing  with  that 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  157 

required  by  the  monoacetate  of  resorcinol,  and  should  be 
readily  soluble  in  cold  dilute  caustic  soda  (freedom  from 
resorcin  diacetate)  . 

w-       Euresol  possesses  an  antiseptic  action  similar  to  that 
of  resorcinol,  but  milder  and    more    lasting, 


b^ing_only_gradually  liberated.  It  is  said  to  be  useful  in 
acne,  scrofula,  chilblains,  and  particularly  in  the  treatment 
of  alopecia  and  seborrhcea. 


OH 

124.  —  Guaiacol  occurs  in  beech  wood  tar,  of  which  it  con- 
stitutes the  fraction  distilling  at  2OO°-205°.  It  is  prepared 
synthetically  according  to  the  following  reactions  : 


0 


N02   _ 

OH  OGH  OCHs  OCH- 


o-nitrophenol.        o-nitroanisol.  o-anisidine.  Guaiacol. 

139  153  123  124 

Preparation  of  o-nitroanisol. — The  following  account  of 
the  preparation  of  o-nitroanisol  by  the  methylation  of 
o-nitrophenol  is  given  by  Jansen  (Chem.  Zeit.  (1913),  12, 171  ; 
Zeits.  Farb.  Ind.  (1913),  12,  247). 

Eighty- three  kilos  of  caustic  soda  solution  (37°  Be.), 
1 80  litres  of  water,  and  75*5  kilos  of  o-nitrophenol  are  placed 
in  a  cast-iron  steam- jacketed  pan  and  evaporated  to  a  thick 
paste.  On  cooling,  the  whole  sets  to  a  thick  cake  (162 
kilos).  One  hundred  and  sixty  kilos  of  this  are  transferred 
to  a  jacketed  autoclave  fitted  with  a  stirrer,  and  60  kilos  of 
anhydrous  sodium  carbonate  and  90  kilos  of  methyl  alcohol 
are  added.  The  autoclave  is  closed,  and  51-5  kilos  of  methyl 
chloride  are  led  in.  The  stirrer  is  kept  going  slowly  for  about 
12  hours.  Steam  is  blown  into  the  jacket  until  a  temper- 
ature of  90°-ioo°  is  recorded,  whereby  the  autoclave  is  kept 
uniformly  at  a  moderate  temperature.  Next  day  the  pressure 
is  released,  the  autoclave  opened,  and  the  contents  are 
transferred  to  a  still  fitted  with  a  stirrer.  About  100  litres 
of  water  are  added  and  the  whole  is  distilled  until  water  alone 


158         ORGANIC  MEDICINAL  CHEMICALS 

passes  over.  The  residue  is  run  into  a  reservoir  half  filled 
with  hot  water  and  left  for  a  day.  The  water  is  then  drawn 
off  and  the  oil  washed  in  a  separator  with  dilute  hydrochloric 
acid.  Sixty  kilos  of  o-nitroanisol  are  obtained,  and  20 
kilos  of  salt  residue,  from  which  more  oil  can  be  extracted  by 
distillation.  (Cain,  Intermediate  Products  for  Dyes,  p.  94.) 
It  can  also  be  prepared  from  o-chloronitro-benzene  (Brand, 
J.pr.  Chem.  (1903),  ii.  67, 145). 

One  hundred  grams  of  o-chloronitro-benzene  are  dissolved 
in  200  c.c.  of  methyl  alcohol  and  a  solution  of  40  grams  of 
potassium  hydroxide  in  200  c.c.  of  water  and  300  c.c.  of  methyl 
alcohol  is  added.  The  mixture  is  boiled  under  a  reflux 
condenser  for  about  26  to  31  hours,  after  which  the  greater 
part  of  the  alcohol  is  distilled  off.  Steam  is  now  blown  in 
and  any  unchanged  o-chloronitro-benzene,  together  with  some 
o-nitroanisol,  is  obtained  in  the  first  20  grams  of  oil  which 
passes  over.  The  remainder  of  the  distillate  consists  of  o-nitro- 
anisol. The  fraction  containing  the  o-chloronitro-benzene 
is  used  again  in  the  next  operation. 

Preparation  of  ortho-anisidine. — The  reduction  of  o-nitro- 
anisol to  o-anisidine  can  be  carried  out  either  with  iron 
and  hydrochloric  acid  or  with  sodium  sulphide,  and  is  effected 
in  the  same  way  as  has  been  described  for  the  reduction 
of  ^>-nitrophenetol  to  ^-phenetidine  (p.  118). 

Guaiacol  from  o-anisidine  (see  D.  R.  PP.  95339;  167211). 
— Twelve  kilos  of  o-anisidine  are  dissolved  in  27  kilos  of 
sulphuric  acid  (36°  Be.)  and  24  kilos  of  water,  mixed  with  50 
kilos  of  ice  and  diazotised  with  a  freshly  prepared  solution, 
which  must  be  absolutely  free  from  chloride,  of  7-5  kilos  of 
sodium  nitrite  in  30  kilos  of  water.  The  temperature  is 
not  allowed  to  exceed  8°. 

The  mixture  is  allowed  to  stand  until  nitrite  can  no  longer 
be  detected.  A  solution  is  prepared  containing  40  kilos 
of  copper  sulphate  cryst.,  40  kilos  of  ammonium  sulphate, 
20  kilos  of  sodium  sulphate,  80  litres  of  water,  and  60  kilos 
of  sulphuric  acid  (36°  Be.) ,  and  heated  to  105°.  In  the  course 
of  2  J  to  3  hours  the  diazo  solution  is  allowed  to  flow  into 
this,  the  temperature  being  maintained  at  105°.  Water  and 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  159 

guaiacol  distil  over  and  are  collected.  When  all  has  been 
added,  steam  is  blown  in  and  distillation  is  continued  until 
no  more  guaiacol  passes  over.  The  distillate,  which  measures 
about  125  litres,  is  made  alkaline,  in  a  copper  vessel,  with  12 
kilos  of  caustic  soda  (36°  Be.)  and  distilled  by  indirect  steam 
until  the  condensate  is  perfectly  clear.  As  the  distillate 
contains  some  guaiacol,  due  to  dissociation  of  the  sodium 
salt,  it  is  used  again  in  the  next  operation.  The  alkaline 
guaiacol  solution  is  now  acidified  by  the  addition  of  15  kilos  of 
sulphuric  acid  (36  °Be.),  the  guaiacol  distilled  over  by  indirect 
steam,  and  separated  mechanically  from  the  distillate.  The 
aqueous  layer  is  mixed  with  the  guaiacol  distillate  obtained 
in  a  subsequent  operation. 

The  copper-ammonium  sulphate  solution  can  be  employed 
for  the  conversion  of  8  to  9  charges  of  diazotised  anisidine, 
after  which  the  copper  is  precipitated  by  the  addition  of  iron 
and  recovered.  The  yield  is  said  to  be  practically  quanti- 
tative. Care  must  be  taken  that  no  metallic  copper  is 
present  during  the  conversion. 

The  separated  guaiacol  contains  2-3  %  of  water  and 
crystallises  only  partially.  It  is  purified  by  distillation  from 
an  enamelled  iron  or  silvered  copper  vessel,  after  being  dried 
over  0-3  to  o -5  %  of  anhydrous  sodium  carbonate.  A  silver 
condenser  and  a  glass  or  earthenware  receiver  are  employed. 


(jo— co- 


GUAIACOL  CARBONATE  (duotal)  I    Jo—CO—  o!    J     274- 

OCH3  OCH3 

— Guaiacol  carbonate  was  first  prepared  by  the  action  of 
phosgene  on  guaiacol,  or  an  alkali  salt  of  guaiacol  (D.  R.  P. 

58129). 


248  99  274 

<S?H3+C°Cl2    -*    (c6H4<gCH3)2CO+2NaCl 
292  99  274 

Several  general  methods  of  carrying  out  the  preparation 


i6o         ORGANIC  MEDICINAL  CHEMICALS 

are  given.  In  one  instance,  2  molecular  equivalents  of 
guaiacol  and  i  equivalent  of  phosgene  dissolved  in  benzene 
are  heated  together  under  pressure  at  150°. 

Equivalent  quantities  of  guaiacol  and  caustic  soda  are 
dissolved  in  water  and  phosgene  led  in  until  the  reaction 
liquor  is  neutral  to  litmus.  The  carbonate,  which  is  insoluble 
in  water,  separates,  and  is  filtered  off,  washed  and  crystallised 
from  alcohol.  Small  yields  are  afforded,  however.  Another 
method  consists  in  dissolving  two  molecular  equivalents  of 
the  phenol  in  toluene  or  benzene,  treating  with  the  necessary 
amount  of  sodium  for  the  formation  of  the  sodium  salt,  and 
then  adding,  with  stirring,  one  equivalent  of  phosgene 
dissolved  in  the  same  solvent.  Reaction  takes  place  without 
the  application  of  heat.  After  it  is  completed  the  solvent 
is  removed  by  direct  or  steam  distillation,  the  guaiacol 
carbonate  washed  with  water  and  recrystallised  from  alcohol. 
As  a  variation  of  this  procedure  sodium  guaiacolate  may  be 
first  prepared,  by  evaporation  of  its  aqueous  solution,  dried 
thoroughly,  and  powdered,  suspended  in  benzol  and  treated 
with  phosgene  as  above. 

A  more  recent  method,  D.  R.  P.  99057,  consists  in  com- 
bining guaiacol  with  ethyl  or  methyl  chloroformate  (prepared 
by  the  action  of  alcohol  on  phosgene)  in  accordance  with 
the  following  equations  : 


/OCH3    0  H  /ONa  CO/OCH3  ,  NaC1 

CO\C1        fC6H4\OCH3  CO\OC6H4OCH3  + 

94-4  146  182 


364  274        90 


or 

182          124 


274        32 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  161 

Two  equivalents  of  gnaiacol  are  dissolved  in  toluene  and 
treated  with  one  equivalent  of  sodium.  The  conversion  into 
sodium  guaiacolate  is  completed  by  boiling,  after  which  the 
solution  is  cooled  and  treated,  whilst  being  stirred,  with  one 
equivalent  of  ethyl  chloroformate.  The  solvent  is  removed 
by  distillation  and  the  residue  heated  up  to  140°,  so  long 
as  any  distillate  is  afforded.  After  cooling,  the  product  is 
washed  with  water  and  recrystallised  from  alcohol. 

In  place   of    chloroformic  ester,   diethyl    or    dimethyl 
carbonate  may  be  employed. 


248  118 


274  92 

Guaiacol  carbonate  is  a  white  crystalline  powder,  without 
taste  or  odour.  M.p.  84°.  It  is  insoluble  in  water  ;  dis- 
solves in  70  parts  of  cold  90  %  alcohol.  The  alcoholic 
solution  should  afford  no  green  colouration  when  treated  with 
ferric  chloride  solution  (absence  of  guaiacol).  No  weighable 
residue  should  be  left  on  ignition. 

Guaiacol  carbonate  is  employed  as  an  intestinal  antiseptic. 
It  is  largely  administered  in  cases  of  phthisis,  and,  particu- 
larly, of  rheumatoid  arthritis,  for  which  it  has  been  highly 
recommended. 

POTASSIUM  GUAIACOL  SULPHONATE  ("  Thiocol  ") 

OH 

242. 


According  to  the  patent  specification,  D.  R.  P.  132645,  mo- 
lecular quantities  of  guaiacol  and  of  concentrated  sulphuric 
acid  are  heated  together  at  a  temperature  not  exceeding  80° 
until  a  test  portion  forms  a  clear  solution  in  water.  After 
cooling,  the  sulphonation  mixture  is  diluted  with  water, 
neutralised  with  potassium  carbonate,  and  the  solution 
i.  ii 


162         ORGANIC  MEDICINAL  CHEMICALS 

saturated  with  potassium  chloride,  whereby  the  potassium 
salt  of  the  sulphonic  acid  is  salted  out. 

The  sulphonation  of  guaiacol  is  preferably,  however, 
carried  out  at  3O°-6o°,  and  the  product,  after  conversion 
into  the  normal  calcium  salt,  is  treated  with  lime  (J  mol. 
CaO  :  i  mol.  guaiacol),  or  the  corresponding  amount  of 
calcium  chloride  in  ammoniacal  solution.  The  resulting 
solution  rapidly  deposits  colourless  prismatic  crystals  of 
basic  calcium  guaiacol-4-sulphonate,  the  salt  of  the  5-sul- 
phonic  acid  remaining  in  solution. 

The  separation  may  also  be  effected  by  means  of  the 
lead  salts.  A  hot  solution  of  the  normal  lead  salts,  when 
treated  with  lead  acetate  corresponding  to  J  mol.  of  PbO, 
gives  a  white  precipitate  which  at  the  boiling  temperature 
contains  only  the  lead  salt  of  guaiacol-4-sulphonic  acid.  This 
is  filtered  off,  and  on  cooling  the  filtrate  the  basic  salt  of 
guaiacol-5-sulphonic  acid  is  obtained.  Rising  (Ber.  (1906), 
39,  3688)  employed  105  %  of  the  theoretical  quantity  of 
sulphuric  acid  and  heated  at  70°  for  15  hours.  The 
sulphonation  mixture  was  diluted  with  water  and  excess  of 
guaiacol  removed  by  distillation  with  steam,  6-5  %  being 
recovered.  Sulphuric  acid  was  then  removed  by  treatment 
with  baryta,  and  the  filtered  solution  neutralised  with  potash 
and  concentrated.  A  crop  of  heavy  crystals  of  the  4-sul- 
OH 

phonate    \     ]P*****  was  obtained,  the  filtrate  from  which 


S03H 

was  evaporated  to  dryness  and  extracted  with  boiling 
alcohol,  from  which  potassium  guaiacol-5-sulphonate  crystal- 
lised on  cooling.  Under  the  above  conditions  57  %  of  the 
4-sulphonic  acid  and  43  %  of  the  5-sulphonic  acid  were 
found  to  be  formed.  Thiocol  was  originally  believed  to  be 

OH 

a    salt    of   guaiacol-6-sulphonic   acid   $°3Hi     i°CH3>  but 

\/ 

was  shown  by  Paul  (Ber.  (1906),  39,  2772)  to  be  mainly 
potassium  guaiacol-5-sulphonate.  The  following  methods, 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  163 

by  which,  it  is  claimed,  a  product  consisting  mainly  of  the 
guaiacol-5-sulphonate  is  formed,  were  then  protected  (D.R.P. 
212389). 

(1)  Finely   powdered   guaiacol   carbonate   is   gradually 
stirred  into  a  slight  excess  of  sulphuric  acid  (66°  Be.),  when 
the  temperature  rises  to  60°.     The  mixture  is  allowed  to 
stand  until  a  test  portion  dissolves  clear  in  water,  after  which 
it  is  diluted  with  water  and  the  guaiacol-5-sulphonic  acid 
carbonate    decomposed   by    heating    at    100°.     Excess  of 
sulphuric  acid  is  removed  by  baryta  or  calcium  carbonate, 
and  the  potassium  salt  prepared  in  the  usual  way. 

Alternatively,  the  sulphonation  mixture  is  diluted  with 
a  little  ice,  when  the  sulphonic  acid  carbonate 

OCH3  OCH3 

Q-oco-oQ 

SO3H  S03H 

separates  as  a  mass  of  needle-shaped  crystals.  It  is 
filtered  off,  washed  with  a  little  concentrated  hydrochloric 
acid  and  dried  at  a  low  temperature.  M.p.  Ii5°-ii7°. 
The  aqueous  solution  evolves  CO2  on  heating,  yielding 
guaiacol-5-sulphonic  acid. 

(2)  One   kilo  of   acetylguaiacol    is   dissolved  in  i  kilo 
of  acetic  anhydride,  and  i  kilo  of  sulphuric  acid  (66°  Be.) 
is    added    gradually,    with    cooling    and    stirring.     After 
standing  for  some  hours,  until  the  reaction  product  dissolves 
completely  in  water,  an  equal  volume  of  water  is  added  and 
the  acetic  acid  removed  by  steam  distillation.     The  aqueous 
solution  is  then  neutralised  with  barium  carbonate   and 
the  potassium  salt  of  guaiacol-5-sulphonic  acid  prepared 
from  the  resulting  barium  salt. 

The  guaiacol-4-sulphonic  acid  obtained  as  a  by-product 
in  the  manufacture  of  thiocol  may  be  reconverted  into 
guaiacol  by  heating  with  phosphoric  or  sulphuric  acids 
(D.  R.  P.  250380).  Twenty  kilos  of  sodium  guaiacol  sul- 
phonate  are  mixed  with  100  kilos  of  24  %  phosphoric  acid 
and  the  mixture  concentrated  until  the  boiling  point  is  over 


164         ORGANIC  MEDICINAL   CHEMICALS 

140°.  Superheated  steam  is  then  blown  in,  when  the 
guaiacol  distils  over.  In  place  of  phosphoric  acid,  sulphuric 
acid  of  b.p.  135°  may  be  employed. 

The  thiocol  obtained  by  any  of  the  above  methods  is 
purified,  if  coloured,  by  recrystallisation  from  water,  employ- 
ing vegetable  charcoal  as  a  decolourising  agent. 

Thiocol  is  a  colourless,  crystalline  powder,  neutral,  or 
faintly  alkaline  to  litmus.  It  is  readily  soluble  in  water, 
slightly  so  in  cold  alcohol.  It  is  important  that  the  salt 
for  therapeutic  use  should  be  free  from  the  4-sulphonate. 
Concentrated  nitric  acid,  added  to  a  10  %  aqueous  solution, 
should  afford  only  a  red  colour.  If  the  4-sulphomc  acid  is 
present  a  yellow  precipitate  of  dinitroguaiacol,  m.p.  122°,  is 
obtained.  Ammoniacal  calcium  or  barium  chlorides,  added 
to  the  aqueous  solution,  should  afford  no  white  precipitate. 

Thiocol  is  employed  for  the  same  purposes  as  guaiacol. 
It  possesses  the  advantages  of  being  comparatively  tasteless, 
non-toxic,  and  of  exercising  no  disturbing  action  on  the 
digestion.  It  is  claimed  to  be  useful  in  treatment  of  diseases 
of  the  respiratory  tract,  incipient  tuberculosis,  and  in  certain 
forms  of  diarrhoea. 

CH3 

THYMOL    (tso-propyl-m-cresol)     Qj,f    I     150. — Thymol 

CH(CH3)2 

occurs  in  the  volatile  oil  from  Ptychotis  ajowan  (fruits) 
(50-60%)  ;  Monarda  punctata  (50-60  %)  ;  Mosula  japonica 
(42  %)  ;  Thymus  vulgaris  (20-50  %) ;  Carum  copticum. 

It  is  prepared  in  Britain  and  India  from  Carum  copti- 
cum ;  in  Germany  also  it  is  said  to  be  made  from  this  source. 
In  America,  however,  it  is  made  from  Monarda  punctata, 
the  phenol  content  of  the  oil  of  which  has  been  improved 
by  cultivation  to  over  seventy  per  cent. 

Thymol  is  isolated  from  the  volatile  oil  by  shaking  the 
latter  with  an  equal  volume  of  warm  sodium  hydroxide 
solution  (sp.gr.  i'33)  and  after  several  hours  the  mixture  is 
diluted  with  2-3  volumes  of  hot  water.  The  aqueous  portion, 
which  contains  the  thymol  in  solution,  in  the  form  of  its 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  165 

sodium  salt,  is  separated  and  acidified.  The  precipitated 
thymol  is  dried  and  rectified  by  distillation.  The  fraction 
which  distils  at  22O°-235°  is  seeded  with  a  crystal  of 
pure  thymol  and  set  aside  in  a  cold  place.  The  crystallised 
thymol  is  separated  by  filtration  and  purified  by  recrystallisa- 
tion  from  petroleum  ether. 

Thymol  forms  large,  colourless,  translucent  rhombic 
prisms,  having  a  characteristic  odour  and  a  burning  taste. 
M.p.  5o°-5i°.  B.p.  230°.  It  is  sparingly  soluble  in  water 
(i  in  1500),  is  very  readily  soluble  in  alcohol,  ether  and 
chloroform,  and  dissolves  in  6  parts  of  petrol-ether.  The 
aqueous  extract  should  be  neutral,  and  not  coloured  violet 
by  ferric  chloride  (absence  of  phenol).  Addition  of  bromine 
water  to  the  extract  should  produce  a  milky  turbidity, 
but  not  a  crystalline  precipitate.  Thymol  should  volatilise, 
without  leaving  a  residue,  at  the  temperature  of  a  steam 
bath. 

Thymol  is  a  powerful  antiseptic.  It  is  employed  as  an 
intestinal  antiseptic  in  diarrhoea  and  typhoid,  and  as  an 
ointment  or  soap  in  the  treatment  of  parasitic  skin  diseases  ; 
also  as  an  inhalant  in  laryngitis.  Like  carbolic  acid,  it  has 
local  anaesthetic  properties.  It  is  also  employed  to  destroy 
intestinal  worms. 

BETA-NAPHTHOL  (beta-monohydroxy-naphthalene) 

OH 

144. 

—  j3-naphthol  is  prepared  by  the  fusion  of  sodium  naphtha- 
Iene-j3-sulphonate  with  caustic  soda.  The  following  account 
of  its  manufacture  is  taken  from  Cain's  The  Manufacture  of 
Intermediate  Products  for  Dyes,  pages  166  and  204.  One 
hundred  kilos  of  naphthalene  are  melted,  heated  to  160°, 
and  100  kilos  of  sulphuric  acid  (66°  Be.)  gradually  added, 
the  temperature  being  kept  constant.  The  mixture  is 
maintained  at  this  temperature  for  a  further  3  hours  and  is 
then  heated  at  170°  for  an  hour  and  subsequently  at  180° 
for  the  same  time.  Three  or  four  kilos  of  naphthalene 
distil  over.  The  reaction  is  finished  when  a  sample  dissolves 


166         ORGANIC  MEDICINAL  CHEMICALS 

completely  in  water.  The  product  is  blown  into  2500 
litres  of  water,  neutralised  with  50-60  kilos  of  lime,  filtered, 
and  the  calcium  salt  converted  into  the  sodium  salt  by 
treating  the  filtrate  with  about  40  kilos  of  sodium  carbonate, 
filtering,  and  evaporating  to  crystallising  point.  The 
sodium  salt  of  the  jS-acid  separates  out,  whilst  the  salt  of 
the  a-acid  remains  in  the  mother  liquor.  It  is  simpler, 
however,  to  salt  out  the  acid,  after  pouring  it  into  2500 
litres  of  water,  by  adding  salt  or  sodium  sulphate,  or  by 
neutralising  with  about  40  kilos  of  sodium  carbonate. 
The  sodium  salt  obtained  in  this  way  is  filtered  in  a  filter 
press  and  dried,  preferably  in  a  vacuum  dryer.  The  yield 
is  about  160-165  kil°s  (Orandmougin,  Rev.  Prod.  Chim. 
(1917),  20,  197). 

One  hundred  kilos  of  caustic  soda  are  melted  with 
20  litres  of  water,  and  at  200°,  160  kilos  of  sodium  naphtha- 
lene j8-sulphonate  are  gradually  added.  The  temperature 
is  then  raised  to  28o°-300°  and  the  fusion  is  complete  in  5 
to  6  hours.  The  liquid  mass  is  then  run  into  2000  litres 
of  water,  and  hydrochloric  acid,  about  100  kilos,  added 
sufficient  to  liberate  the  naphthol,  but  not  to  decompose 
the  sodium  sulphite. 

Alternatively,  the  sodium  j3-naphthoxide  is  allowed  to 
settle  out  on  the  surface  of  the  fusion  mixture  and  then 
separated,  when  the  mixture  of  sodium  hydroxide  and 
sodium  sulphite  may  be  used  for  neutralising  the  sulphonation 
mixture  (B.  P.  2300/1883).  The  naphthol  is  filtered  in  a 
filter  press,  dried,  and  distilled  in  a  vacuum.  The  first 
runnings  are  separated  from  the  main  distillate  and  about 
10-15  %  of  the  weight  of  naphthol  remains  behind  as  tar. 
Yield  80  kilos.  By  another  method  (F.  P.  469040)  sodium 
naphthalene- j8-sulphonate,  46  parts,  is  treated  in  an  autoclave 
with  50  parts  of  sodium  hydroxide,  40°  Be.,  for  10-20  hours 
at  300°-330°.  The  j8-naphthol  is  separated,  after  cooling, 
as  described  above.  It  has  been  stated  also  (Ber.  (1914), 
47,  3160)  that  10  %  sodium  hydroxide  at  300°  will  effect 
the  conversion.  Distillation  by  means  of  superheated 
steam  may  also  be  employed  for  the  purification  of  jS-naphthol. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  167 

It  is  obtained  finally  in  the  form  required  for  pharmaceutical 
purposes  by  crystallisation  from  dilute  alcohol. 

Beta-naphthol  is  marketed  in  the  form  of  almost  white 
crystalline  laminae,  or  as  a  nearly  white  crystalline  powder. 
M.p.  122°.  B.p.  286°  at  atmospheric  pressure. 

It  is  very  sparingly  soluble  in  water,  and  dissolves  in  2 
parts  of  alcohol  (90  %).  On  account  of  its  susceptibility 
to  light  it  should  be  kept  in  the  dark ;  and  it  should  also 
be  as  far  as  possible  protected  from  air. 

The  solution  in  aqueous  alcohol  should  be  neutral  in 
reaction  towards  litmus.  A  cold  saturated  aqueous  solution 
should  not  afford  a  violet  colour  with  calcium  hypochlorite 
solution  (absence  of  alpha-naphthol) .  A  method  for  deter- 
mining the  alpha-naphthol  content  of  beta-naphthol  is  given 
in  the  Journ.  Soc.  Chem.  Ind.  vol.  xvi.,  p.  295. 

When  ignited,  no  weighable  residue  should  be  left ;  com- 
plete solution  should  be  effected  in  50  parts  of  10  %  aqueous 
ammonia,  and  the  solution  should  not  have  a  deeper  colour 
than  pale  yellow. 

Beta-naphthol  is  employed  internally  as  an  intestinal 
antiseptic,  and  externally,  in  the  form  of  ointment,  for  the 
treatment  of  eczema  and  parasitic  skin  diseases.  It  is 
prescribed  in  typhoid  and  intestinal  dyspepsia,  and  in 
summer  diarrhoea  of  children.  Prolonged  administration, 
especially  of  large  doses,  may  lead  to  nephritis. 

CHLORAMINE-T  (sodium  toluene  ^-sulphonchloramine) 
CH3<(^>SO2NNaCl+3H2O.  281-4.— The  use  of  this  sub- 
stance as  a  disinfectant  was  introduced  recently  by  Dakin 
and  his  colleagues.  A  method  for  its  preparation  has 
been  described  in  some  detail  by  Inglis  (J. S.C.I.  (1918), 
37,  288  T).  Toluene  was  the  starting  point,  being  converted 
into  toluene-^>-sulphonic  acid,  the  sodium  salt  of  which,  when 
treated  with  phosphorus  pentachloride,  afforded  toluene- 
/>-sulphonchloride.  This  substance,  however,  is  a  cheap 
and  plentiful  by-product  obtained  in  the  production  of 
saccharin  (see  this) ,  in  connection  with  which  its  manufacture 
is  described. 

Inglis  converted  toluene-/>-sulphonchloride  into  toluene 


i68         ORGANIC  MEDICINAL    CHEMICALS 

/>-sulphonamide  by  interaction  with  a  large  excess  of  0*880 
ammonia  in  a  pressure  vessel  (100  c.c.  of  ammonia  to  100 
grams  of  sulphonchloride),  the  reaction  taking  place  spon- 
taneously, with  considerable  evolution  of  heat. 


34  171  53'4 


In  practice,  the  use  of  diluted  ammonia,  in  an  open  vessel, 
is  found  to  be  possible,  whilst  only  a  small  excess  is  required. 
Into  an  iron  vessel  provided  with  an  efficient  stirrer  are 
introduced  320  parts  of  6  %  aqueous  ammonia  solution  (ca.  7  % 
excess),  to  which  are  added  100  parts  of  toluene-/>-sulphon- 
chloride.  Stirring  is  continued  until  a  filtered  sample  of  the 
solid  develops  no  acidity  on  being  boiled  with  water.  The 
toluene  ^-sulphonamide  is  then  filtered  off  by  means  of  a 
centrifugal  machine  and  washed  with  water.  The  liquor, 
which  contains  ammonium  chloride,  is  alkalised  with  lime 
and  distilled,  in  order  to  recover  the  ammonia. 

The  method  given  by  IngHs  (loc.  cit.)  for  the  conversion 
of  toluene-^-sulphonamide  into  chloramine-T  is  carried  out 
as  follows  :  Toluene-/>-sulphonamide,  171  parts  (i  mol.), 
is  added  to  525  parts  of  a  2N  solution  of  sodium  hypochlorite 
(1*05  mol.)  containing  40  parts  of  caustic  soda  (i  mol.),  and 
is  dissolved  by  gentle  warmth.  On  cooling,  the  sodium 
toluene  ^-chlorsulphonamide  (chloramine-T)  separates  as 
a  mass  of  colourless  crystals.  It  is  filtered  off,  washed  with 
a  little  brine,  recrystallised  from  twice  its  weight  of  hot 
water,  being  allowed  to  cool  without  stirring,  and  dried 
finally  at  35°-4o°. 


193  227-4 

The  filtrate  from  the  crude  chloramine-T,  which  is  satu- 
rated with  the  salt,  and  contains  the  whole  of  the  caustic 
soda  taken,  is  used  for  a  subsequent  operation,  being  mixed 
with  i  molecular  proportion  of  sodium  hypochlorite  and 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  169 

employed  for  converting  into  chloramine-T  a  further  mole- 
cular equivalent  of  toluene-/>-sulphonamide.  The  nitrate 
from  the  recrystallisation  of  the  chloramine-T  is  used 
repeatedly  for  the  same  purpose  until  too  highly  coloured. 
The  chloramine-T  contained  in  the  liquors  which  can  no 
longer  be  used,  is  recovered  in  the  form  of  toluene-^>-sulphon- 
amide  by  treatment  with  sodium  bisulphite,  together  with 
acid  to  neutralise  any  free  caustic  soda  present. 


104 


171 

Chloramine-T  forms  colourless  needles,  possessing  a 
characteristic  chlorous  odour.  It  dissolves  in  15  parts  of 
cold,  and  is  readily  soluble  in  hot,  water.  The  solution  is 
neutral  to  phenolphthalein,  and  may  be  boiled  without 
decomposition. 

A  weighed  quantity,  dissolved  in  water,  treated  with 
potassium  iodide  and  hydrochloric  acid,  and  titrated  with 
standard  thiosulphate  solution,  should  be  found  to  contain 
not  less  than  12*3  %  of  active  chlorine.  A  perfectly  bright 
solution  (10  %)  should  be  formed  in  normal  saline  (0-9  % 
NaCl). 

Chloramine-T  is  a  powerful  disinfectant  and  has  been 
used  with  success  in  the  treatment  of  practically  all  external 
infectious  conditions  of  the  body,  and  for  disinfecting  the 
nose,  throat,  and  mouth,  and  the  uterine  and  urethral 
passages. 

Chloramine-T  has  been  extensively  used,  during  the  war, 
for  the  treatment  of  wounds.  It  possesses  a  very  high 
germicidal  coefficient  and  is  superior  in  many  respects  to 
the  commonly  employed  organic  germicides,  phenol,  iodo- 
form,  lysol,  etc.  It  is  comparable  in  efficiency  with  sodium 
hypochlorite,  but  possesses  over  this  substance  the  advan- 
tages of  certainty  of  composition  and  complete  stability. 


170         ORGANIC  MEDICINAL   CHEMICALS 
Dichloramine-T  (toluene-/>-sulphondichloramine) 
CH3<3)S02NC12.     239-8. 

—  This  substance  was  first  prepared  by  Chattaway  (Trans. 
Chem.  Soc.  (1905),  87,  145),  two  methods  being  employed. 
In  the  one,  chlorine  was  passed  through  a  solution  of 
toluene-^-sulphonamide  in  caustic  soda  ;  in  the  other  an 
alkaline  solution  of  toluene-^>-sulphonamide  was  added  to 
an  excess  of  a  saturated  solution  of  bleaching  powder,  and 
the  dichloramine  precipitated  by  acidification  with  acetic 
acid. 

A  modification  of  the  latter  method  is  most  suited  for 
technical  application.  One  may  start  with  either  sodium 
toluene-sulphonchloramine  (see  under  chloramine-T)  or 
toluene-^-sulphonamide  ;  in  the  former  case  one  molecular 
equivalent,  in  the  latter  case  two,  of  hypochlorite  will  be 
required. 


239-8 

Chloramine-T,  281*4  parts  (i  mol.),  is  dissolved  in  water, 
2800  parts,  mixed  with  500  parts  of  2N  sodium  hypochlorite 
solution  (i  mol.)  and  cooled  to  o°.  Hydrochloric  acid  is 
added,  with  stirring,  the  amount  required  being  2  mole- 
cular proportions,  in  addition  to  the  quantity  necessary  to 
neutralise  the  alkalinity  of  the  hypochlorite  solution. 
Dichloramine-T  is  precipitated  in  the  form  of  a  white  powder, 
and  is  filtered  off,  washed  with  water,  and  dried  at  atmo- 
spheric temperature. 

It  may  be  obtained  in  the  form  of  yellow-tinted,  heavy, 
acicular  crystals  by  recrystallisation  from  chloroform  or 
carbon  tetrachloride. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  171 

Dichloramine-T  is  a  white  or  faintly  yellow-tinted 
crystalline  powder.  It  is  almost  insoluble  in  water,  but 
readily  soluble  in  most  organic  solvents,  except  petroleum, 
in  few  of  which,  however,  is  it  stable. 

A  weighed  quantity  dissolved  in  glacial  acetic  acid  and 
treated  with  potassium  iodide  and  titrated  with  standard 
thiosulphate  solution  should  show  a  content  of  not  less  than 
29-0  %  of  active  chlorine. 

Dichloramine-T  is  usually  employed  dissolved  in  chlori- 
nated eucalyptol,  or  "  chlorcosane,"  a  chlorinated  paraffin 
wax  (B.  M.  /.,  I2th  January,  1918). 

It  should  form  a  bright  solution  in  these  solvents,  which 
are  the  best  Dakin  could  find  for  preparing  a  stable  solution 
suitable  for  practical  use. 

Oily  solutions  of  dichloramine-T  are  employed  for 
nasopharyngeal  disinfection,  and  in  the  treatment  of  in- 
fected wounds,  of  boils  and  carbuncles,  etc.  Applied  in 
this  way  dichloramine-T  has  a  greater  and  more  prolonged 
germicidal  action  than  that  of  any  other  compound.  It 
possesses  the  power  of  being  able  to  dissolve  dead  tissues, 
and  does  not  coagulate  protein,  so  that  a  deep-seated 
sterilisation  of  the  wound  is  ensured. 

HALAZONE  (^-dichlorsulphonamino-benzoic  acid) 


>.     269-8. 

— The  preparation  of  halazone  was  first  described  by  Dakin 
and  Dunham  (Brit.  Med.  J.,  26th  May,  1917).  Toluene 
^-sulphonamide  is  oxidised  to  ^-sulphonamino-benzoic  acid, 
and  this,  dissolved  in  caustic  soda,  is  chlorinated  by  passing 
through  it  a  current  of  chlorine  gas.  A  more  convenient 
method  consists  in  treating  it  with  sodium  hypochlorite  and 
hydrochloric  acid. 

CH3C6H4S02NH2    ->    COOHC6H4S02NH2 

171  201 

COOHC6H4S02NH2+2NaOCl+2HCl 

201 


269-8 


172         ORGANIC  MEDICINAL   CHEMICALS 

One  hundred  parts  of  toltiene-^-sulphonamide  are  added 
to  a  mixture  of  250  parts  of  sodium  bichromate,  370  parts 
of  concentrated  sulphuric  acid,  and  600  parts  of  water,  and 
the  whole  boiled  for  an  hour.  After  cooling,  the  crude 
sulphonamino-benzoic  acid  is  filtered  off,  washed  with  water, 
and  dissolved  in  hot  diluted  caustic  soda.  The  solution  is 
filtered  and  whilst  still  hot  the  acid  is  reprecipitated  by 
addition  of  hydrochloric  acid,  separated  by  filtration,  and 
well  washed. 

One  hundred  parts  of  sulphonamino-benzoic  acid  are 
dissolved  in  500  parts  of  N/i  caustic  soda  (i  mol.),  the 
solution  cooled  to  o°  and  mixed  with  500  parts  of  14*9  % 
sodium  hypochlorite,  or  its  equivalent  (2  mols.). 

With  continued  stirring  and  cooling  are  added  500  parts 
of  2N  hydrochloric  acid  plus  the  quantity  necessary  to 
neutralise  the  alkalinity  of  the  hypochlorite  solution.  The 
temperature  is  kept  below  5°  throughout.  The  halazone, 
which  is  precipitated  as  a  light,  white,  crystalline  powder,  is 
filtered  off,  washed  with  water,  and  dried  at  atmospheric 
temperature. 

Halazone  is  a  white,  chalky  powder,  insoluble  in  water. 
M.p.  213°.  It  dissolves  in  cold  sodium  carbonate  or 
bicarbonate,  from  which  it  is  reprecipitated  unchanged  by 
acid. 

Halazone  contains  26*2  %  of  active  chlorine  ;  O'l  gram 
dissolved  in  glacial  acetic  acid  and  treated  with  potassium 
iodide  should  require  from  14-8  to  14-9  c.c.  of  decinormal 
thiosulphate  solution  for  combination  with  the  liberated 
iodine. 

Halazone  was  introduced  as  a  water  sterilising  agent, 
being  for  this  purpose  extraordinarily  efficacious.  Its 
germicidal  power  is  such  that  at  a  concentration  of  i  in 
300,000  it  destroys  the  organisms  of  cholera,  typhoid,  coli, 
and  dysentery,  even  in  heavily  contaminated  water,  in  about 
30  minutes. 

Halazone  is  usually  mixed  with  dry  sodium  car- 
bonate, sodium  bicarbonate,  or  borax,  and  made  up  into 
tablet  form. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  173 

OH 

TRIBROMPHENOL  (bromol)       Brf  JBr      331.— Tribrom- 

Br 

phenol    can    be   prepared    (Ann.    137,    209)    by    dropping 
bromine  into  cooled,  stirred  phenol. 

C6H5OH+3Br2    ->     C6H2Br3OH+3HBr 
94  48o  331  243 

Theoretical  quantities  are  used,  and  the  completion  of 
the  reaction  is  hastened  by  warming.  A  hard,  yellow, 
crystalline  mass  is  obtained.  It  is  crushed,  washed  with 
water  until  neutral,  and  dissolved  in  an  equal  weight  of  hot 
alcohol.  The  solution  is  filtered,  and  water  is  added,  just 
short  of  the  point  of  forming  a  permanent  turbidity.  The 
tribromphenol  crystallises  out  on  cooling  in  the  form  of 
long,  fine  needles. 

Tribromphenol  is  colourless  to  faintly  yellow.  M.p.  95°. 
It  is  soluble  in  2  parts  of  90  %  alcohol,  insoluble  in  water  ; 
dissolves  in  caustic  alkali  solution. 

Tribromphenol  possesses  considerable  antiseptic 
properties.  It  is  employed  mainly  in  the  form  of  its 
bismuth  salt. 

Bismuth  tribromphenolate  (Xeroform). — Thirty  kilos 
of  tribromphenol  are  dissolved  in  150  litres  of  water  con- 
taining 4  kilos  of  sodium  hydroxide,  and  12  kilos  of  bismuth 
nitrate  are  added  to  the  solution  (D.  R.  P.  78889).  The 
reaction  product  is  filtered,  washed  and  extracted  with 
alcohol,  to  remove  free  tribromphenol.  The  extracted 
substance  is  stated  to  yield,  after  drying,  50  %  of  Bi2O3  on 
ignition.  The  commerical  product,  however,  yields  from 
57  to  61  per  cent,  of  bismuth  oxide  (Squire  Compend.  B.  P.) . 
This  corresponds  to  the  formula 

C6H2Br3OBi(OH)2+JBi2O3  (requires  57-4  %  Bi2O3) 

To  produce  this  compound  two  equivalents  of  bismuth 
nitrate  are  required  for  one  equivalent  of  tribromphenol, 


174         ORGANIC  MEDICINAL  CHEMICALS 

whereas,  according  to  the  figures  given  above,  rather  less 
than  one  equivalent  is  employed  (even  supposing  the  bismuth 
nitrate  to  be  calculated  as  anhydrous),  and  a  considerable 
proportion  of  the  tribromphenol  must  be  recovered.  These 
facts  suggest  that  different  proportions  of  the  ingredients  are, 
or  could  advantageously  be,  used. 

Bismuth  tribromphenolate  is  a  yellow  powder,  insoluble 
in  water  and  in  alcohol.  It  should  yield  on  ignition,  as 
stated  above,  57  to  61  per  cent,  of  bismuth  oxide. 

It  is  a  non-irritating  antiseptic,  and  is  employed  as  a 
dressing  for  wounds  and  in  the  treatment  of  ulcers. 

IODOFORM  CHI3.  394. — lodoform  is  prepared  by  the 
action  of  iodine  on  an  alkaline  solution  of  diluted  alcohol 
or  acetone,  and  also  by  the  electrolysis  of  a  solution  of 
potassium  iodide  in  dilute  alcohol. 

From  alcohol  and  iodine :  A  solution  of  32  parts  of 
potassium  carbonate  in  80  parts  of  water  and  16  parts  of 
95  %  alcohol  is  warmed  to  70°  and  treated  gradually, 
whilst  stirring,  with  32  parts  of  powdered  iodine.  lodoform 
separates  as  a  yellow  crystalline  powder,  and,  after  the 
solution  has  become  completely  decolourised,  is  filtered  off, 
washed  with  water  and  dried  at  atmospheric  temperature, 
The  filtrate  is  treated  with  2-3  parts  of  potassium  bichro- 
mate and  16-24  parts  of  concentrated  hydrochloric  acid, 
and  then  neutralised,  after  which  are  added  32  parts  of 
potassium  carbonate^  16  parts  of  95  %  alcohol,  and  6  parts 
of  iodine,  when,  on  warming  at  70°,  a  further  quantity  of 
iodoform  is  produced  (Rother,  Jahresbericht,  1894,  317). 

Beilstein  recommends  the  following  proportions  in  place 
of  the  above  : — 7-5  parts  potassium  carbonate  ;  50  parts  of 
water  ;  8  parts  of  94  %  alcohol ;  10  parts  of  iodine  ;  the 
operation  being  carried  out  in  the  same  way  as  before. 

From  acetone  and  iodine :  One  hundred  parts  of  iodine 
are  dissolved  in  320  parts  of  warmed  10  %  caustic  soda 
solution.  After  cooling,  20  parts  of  acetone  are  introduced, 
followed  by  100  parts  of  powdered  iodine.  Caustic  soda 
liquor  is  added,  in  small  amounts  at  a  time,  until  the  iodine 
has  disappeared.  When  cold,  the  iodoform  is  filtered  off. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  175 

The  filtrate  is  treated  with  20  parts  of  acetone,  acidified  with 
hydrochloric  acid,  and  then  made  alkaline  again  with 
caustic  alkali.  The  two  operations  are  repeated  until  the 
addition  of  acid  no  longer  gives  a  precipitate  of  iodine. 
Then,  by  careful  addition  of  a  hypochlorite  solution  and  of 
caustic  soda  a  further  precipitation  of  iodoform  is  obtained. 
Total  yield  180  parts.  It  is  purified  by  recrystallisation 
from  alcohol. 

By  electrolysis:  According  to  D.  R.  P.  29771,  50  kilos 
of  potassium  iodide  are  dissolved  in  300  kilos  of  water  and 
30  kilos  of  96  %  alcohol.  The  solution  is  electrolysed 
whilst  warm,  CO2  being  led  in. 

Elbs  (Electrolytic  Preparations)  gives  a  process  in  more 
detail.  Electrodes  of  platinum  gauze  (anode)  and  foil 
(cathode)  are  employed,  and  a  current  density  of  i  to  3  amps, 
per  100  sq.  cm.  The  electrolyte  consists  of  20  grams  of 
sodium  carbonate  (anhydrous),  20  grams  of  potassium 
iodide,  50  c.c.  of  96  %  alcohol  in  200  c.c.  of  water.  It  is 
heated  at  5o°-70°  and  a  current  of  CO2  passed  through, 
between  the  anode  and  cathode,  whilst  electrolysis  proceeds. 
The  correct  rate  of  passage  of  the  CO2  is  recognised  by  the 
solution  being  maintained  at  a  light  to  dark  yellow  colour  ; 
if  it  should  become  brown  from  the  separation  of  free  iodine 
the  stream  of  gas  is  interrupted  for  a  time.  The  iodine  is 
filtered  off,  washed  with  water,  and  dried  at  ordinary 
temperature,  the  solution  being  used  again  after  the  addition 
of  fresh  quantities  of  alcohol  and  potassium  iodide.  A 
current  efficiency  of  80  %  may  thus  be  obtained. 

A  careful  study  of  the  process  was  made  by  Foerster  and 
Meves  (J.  pr.  Chem.  (1897),  256,  354).  An  anode  of  platinum 
was  employed,  and  a  cathode  of  lead,  the  latter  being 
enveloped  in  parchment  paper.  The  electrolyte  consisted 
of  400  c.c.  of  an  aqueous  solution  containing  60  grams  of 
potassium  iodide,  20  grams  of  sodium  carbonate  (anhydrous) 
and  80  c.c.  of  96  %  alcohol.  The  temperature  was  main- 
tained at  6o°-65°  and  CO2  was  passed  in.  The  optimum 
current  density  was  found  to  be  i  amp.  per  100  sq.  cm., 
when  a  current  efficiency  of  95-97  %  was  obtained.  At 


176         ORGANIC  MEDICINAL  CHEMICALS 

2  amps,  the  efficiency  was  80-93  % ;    at  3  amps,  it  fell  to 

73-79  %• 

The  following  equations  have  been  given  to  represent 

the  formation  of  iodoform  : — 

C2H5OH+5I2+H20    ->    CHI3+C02+7HI 
C2H5OH+4l2+H20    ->   CHI3+HCOOH+5H1 

Iodoform  is  supplied  in  the  form  of  small,  lemon-yellow, 
hexagonal  crystals,  and  as  a  crystalline  powder.  It  possesses 
a  characteristic  odour  and  taste.  M.p.  115°.  It  is  very 
sparingly  soluble  in  water  ;  dissolves  in  120  parts  of  90  % 
alcohol,  in  14  parts  of  chloroform,  and  in  7  parts  of  ether. 

When  treated  with  water  i  :  10  and  filtered,  the  filtrate 
should  be  colourless,  possess  no  bitter  taste,  yield  only 
a  faint  opalescence  with  silver  nitrate,  and  be  unaffected 
by  barium  nitrate  solution.  It  should  also  be  neutral  in 
reaction.  Iodoform  is  required  to  dissolve  completely  in 
chloroform  and  the  solution  should  be  bright.  A  turbidity 
usually  indicates  the  presence  of  moisture. 

Iodoform  is  a  very  generally  used  antiseptic  and  de- 
odorant. It  has  also  local  anaesthetic  properties.  Internally 
it  is  administered  in  cancer,  to  relieve  the  pain,  and  as  a 
suppository  in  chronic  prostatis,  haemorrhoids,  and  anal 
fissure.  Externally  it  is  applied  to  burns,  and  to  cleanse 
foul  ulcers  and  sores  of  venereal  origin. 

TETRA-IODO-PYRROL  (iodol). 

1C— CI 

II    I! 

1C    CI         571- 
V 
NH 

— One  part  of  pyrrol  is  stirred  with  150  to  300  parts  of 
water  containing  2*4  parts  of  caustic  soda.  An  aqueous 
solution  containing  15  parts  of  iodine  and  20  parts  of  sodium 
iodide  is  then  added,  until  the  liquid  is  slightly  brown 
(contains  free  iodine).  The  precipitate  is  filtered  off,  washed, 
and  dissolved  in  alcohol.  The  alcoholic  solution  is  de- 
colourised by  boiling  with  animal  charcoal,  filtered,  and 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  177 

treated  with  water,  when  the  iodol  is  reprecipitated 
(D.  R.  P.  35130). 

Iodol  forms  a  light-brown  powder,  having  a  faint  odour. 
It  is  insoluble  in  water,  dissolves  in  18  parts  of  90  %  alcohol, 
in  ij  parts  of  ether,  and  in  150  parts  of  chloroform. 

It  should  contain  no  free  iodine,  and  a  filtered  aqueous 
extract  should  not  afford  a  reaction  with  silver  nitrate 
solution. 

Iodol  is  employed  as  a  substitute  for  iodoform.  It  is 
devoid  of  objectionable  smell  and  is  stated  to  be  less  poisonous 
than  the  latter  substance. 

IODIPIN  (iodised  sesame  oil). — lodipin  may  be  taken  as 
a  typical  representative  of  a  class  of  iodised  unsaturated 
fats.  It  is  sold  in  mixtures  containing  varying  amounts 
(5  %>  10  %,  and  20  %)  of  iodine. 

According  to  the  original  patent  specification,  D.  R.  P. 
96495,  10  kilos  of  sesame  oil  are  treated  at  4O°-5o°,  whilst 
being  stirred,  with  a  solution  of  1-3  kilos  of  iodine  mono- 
chloride  in  10  litres  of  alcohol.  The  iodised  fat  is  washed 
several  times  with  warm  alcohol  and  dried  in  vacuo  at 
50°.  The  product  yielded  by  taking  the  above  proportions 
is  stated  to  contain  7-5  %  of  iodine. 

By  a  variation  of  the  above  method  a  mixture  of  170 
grams  of  potassium  nitrite  and  166  grams  of  potassium  iodide 
is  treated  with  the  theoretically  necessary  quantity  of 
concentrated  hydrochloric  acid, 

2KNO2+KI+4HC1    ->     ICl+3KCl-f2H2O+2NO 

and  one  litre  of  alcohol  is  added.  The  precipitated  potassium 
chloride  is  filtered  off,  and  the  solution  used,  in  the  manner 
described  above,  for  the  iodisation  of  i  kilo  of  sesame  oil. 

Hydriodic  acid  can  also  be  used  for  the  iodisation  (D.  R.  P. 
135835).  Sesame  oil  is  treated,  at  5°  to  10°,  with  gaseous 
hydriodic  acid ;  by  this  method  products  containing  up  to 
30  %  of  iodine  can  be  obtained.  A  further  method  is  given 
by  D.  R.  P.  159748.  Into  a  well-stirred  mixture  of  5  kilos 
of  sesame  oil,  2  litres  of  water,  and  300  grams  of  finely- 
powdered  iodine,  sulphur  dioxide  is  passed,  until  the  iodine 

I  12 


178         ORGANIC  MEDICINAL   CHEMICALS 

colour  has  nearly  disappeared.  By  this  process  a  fat 
containing  5  %  of  iodine  is  obtained.  According  to  the 
quantity  of  iodine  they  contain  iodipin  preparations  varying 
from  a  pale  straw-coloured  oily  liquid  to  a  yellowish-brown 
viscous  fluid  are  obtained.  They  are  insoluble  in  water  and 
in  alcohol  (90  %),  but  dissolve  in  all  proportions  of  ether  and 
of  chloroform. 

Iodipin  is  employed,  by  oral  or  by  hypodermic  adminis- 
tration, in  syphilis  and  syphilitic  affections  ;  also  in 
gonorrhceal  rheumatism,  bronchial  asthma,  bronchitis, 
emphysema  and  pleurisis.  It  is  stated  to  be  well  tolerated 
and  to  produce  no  iodism  or  depression. 

SOZOIODOL  (di-iodo-phenol-^-sulphonic  acid) 


426. 
S03H 

—  Di-iodo-phenol-/>-sulphonic  acid  is  prepared  by  the  action 
of  iodine  upon  phenol-par  a-sulphonic  acid.  Potassium 
iodide  and  potassium  iodate  with  acid  may  be  used  to 
generate  the  iodine,  when  the  sparingly  soluble  potassium 
salt  is  directly  obtained  ;  or  a  mixture  of  sodium  iodide  and 
sodium  hypochlorite  and  acid,  when  either  the  product  may 
be  precipitated  as  the  insoluble  barium  salt,  or  the  solution 
may  be  evaporated  if  the  sodium  salt  is  required. 

(i) 
(2) 


174  300 


448 

Another  process  (D.  R.  P.  45226)  consists  of  acting  upon 
a  solution  of  the  potassium  salt  of  phenol-^>-sulphonic  acid 
with  iodine  mono-chloride,  when  a  mixture  of  the  mono- 
and  di-phenol-^-sulphonic  acids  is  obtained, 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  179 


+3HC1 
S03K  XS03K 

Of  these  the  second  method  is  the  one  likely  to  be 
employed  in  practice,  and  this  only,  therefore,  will  be 
described. 

To  a  solution  of  17*4  parts  (i  mol.)  of  phenol-^-sulphonic 
acid  in  100  parts  of  water  containing  30  parts  (2  mols.)  of 
sodium  iodide,  are  added,  with  continuous  stirring,  the 
equivalent  of  100  c.c.  of  a  14-9  %  solution  of  sodium  hypo- 
chlorite  (2  mols.),  followed  by  the  calculated  quantity  of 
5N.  hydrochloric  acid  required  to  furnish  one  molecular 
equivalent  of  acid  and  to  neutralise  the  free  alkali  contained 
in  the  hypochlorite  solution.  The  neutral  reaction  mixture, 
in  which  the  sozoiodol  is  contained  as  sodium  salt,  is 
treated  according  to  the  salt  which  is  required.  Potassium, 
zinc,  or  mercury  salts,  all  of  which  are  sparingly  soluble,  can 
be  prepared  by  double  decomposition.  The  sodium  salt  is 
obtained  by  concentration  of  the  solution,  and  crystallisa- 
tion ;  whilst  the  free  acid  is  prepared  by  precipitating  the 
insoluble  barium  salt  by  treatment  with  barium  chloride, 
and  decomposing  this  with  the  necessary  amount  of  sulphuric 
acid.  Bi-iodo-phenol-^-sulphonic  acid  is  a  white  crystalline 
powder,  soluble  in  water. 

Sodium  di-iodo-phenol-_/>-sulphonate  dissolves  in  14  parts 
of  water.  Potassium  di-iodo-phenol-^-sulphonic  acid  dis- 
solves in  100  parts  of  water.  Mercury  di-iodo-phenol- 
^>-sulphonate  (mercury  sozoiodol)  is  an  orange-yellow 
amorphous  powder,  insoluble  in  water  but  soluble  in  sodium- 
chloride  solution. 

Sozoiodol  and  its  salts  are  used  as  disinfectants,  chiefly 
locally,  in  nasal  and  pharyngeal  disorders,  and  in  parasitic 
skin  infections.  The  mercury  salt  has  been  employed  in 
syphilis  and  psoriasis,  by  hypodermic  injection  of  its  solution 
in  aqueous  sodium  chloride. 


ARISTOL  (di-iodo-thymol)    C6H2I(-C3H7.—  A  solution  of 

XOI 


i8o         ORGANIC  MEDICINAL  CHEMICALS 

five  kilos  of  thymol  in  10  litres  of  water  containing  1-2 
kilos  of  caustic  soda  is  added,  at  I5°-20°,  with  good  stirring, 
to  a  solution  of  6  kilos  of  iodine  and  9  kilos  of  potassium 
iodide  in  10  litres  of  water. 

A  voluminous  dark  reddish-brown  precipitate  is  formed  ; 
it  is  filtered  off,  washed  with  water,  and  dried  at  atmospheric 
temperature  (D.  R.  P.  49739).  The  compound  may  also 
be  prepared  by  the  action  of  sodium  or  calcium  hypo- 
chlorite,  and  acid,  upon  a  solution  of  sodium  thymolate 
containing  a  soluble  iodide. 


C6H3^C3H7  +2NaOCl +2NaI  +3HC1 
ONa  300 

172  CHg 

->     C6H2IfC3H7+5NaCl+2H20 
XOI 
402 

Aristol  is  a  bulky,  bright-yellowish,  or  reddish-yellow 
powder,  possessing  a  slight  odour  resembling  that  of  iodof orm. 
It  is  insoluble  in  water,  slightly  soluble  in  alcohol,  readily 
soluble  in  ether  and  chloroform.  A  filtered  aqueous  extract 
should  be  neutral  to  litmus  and  should  not  give  a  blue  colour 
with  starch  solution,  indicating  absence  of  free  iodine. 
Twenty  c.c.  of  water  shaken  with  0*1  gram  and  filtered 
should  not  afford  more  than  a  faint  opalescence  on  the 
addition  of  nitric  acid  and  silver  nitrate  solutions. 

Aristol  is  used  as  a  substitute  for  iodoform.  It  has  been 
employed  with  success  in  ulcerating  lupus,  pyrrhcea,  and 
syphilitic  ulcers,  in  the  form  of  a  10  %  ointment  or  as  a 
dusting  powder.  A  solution  (10  %)  in  flexible  collodion  is 
applied  in  poisonous  eczema. 

Loretin  (iodo-8-oxyquinoline-5-sulphonic  acid) 

S03H 


35i. 
OHN 

— One  part  of    8-oxyquinoline  (see  chinosol)  is  dissolved, 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  181 

at  below  o°,  in  6  to  8  parts  of  fuming  sulphuric  acid. 
After  being  allowed  to  stand  for  24  hours  the  mixture  is 
poured  on  to  crushed  ice.  A  copious  precipitate  is  obtained 
in  the  form  of  fine  needles.  This  consists  of  8-oxyquinoline- 
5-sulphonic  acid.  It  is  filtered  off  and  may  be  purified  by 
recrystallisation  from  dilute  hydrochloric  acid.  Forty  parts 
of  the  acid  are  dissolved  in  a  boiling  solution  of  12  parts  of 
potassium  carbonate  and  27*5  parts  of  potassium'iodide  in  350 
to  400  parts  of  water.  With  constant  stirring  and  uninter- 
rupted boiling  are  added,  in  four  or  five  separate  portions, 
46-8  parts  of  bleaching  powder  (25  %).  Boiling  is  continued 
for  15  to  20  minutes  after  addition  of  the  bleaching  powder 
is  completed.  A  thick  yellow  paste  results.  This  is  cooled 
in  an  ice  and  salt  mixture,  and,  with  good  stirring  and  at  a 
low  temperature,  100  vols.  of  hydrochloric  acid  (sp.gr.  1*025) 
are  added,  followed  by  45  vols.  of  concentrated  hydro- 
chloric acid.  A  homogeneous  red  paste  is  obtained,  which 
consists  of  the  calcium  salt  of  iodo-oxyquinoline-sulphonic 
acid.  After  being  allowed  to  stand  overnight  it  is  filtered 
off  and  washed  with  cold  water.  The  free  acid  is  obtained 
as  a  heavy,  yellow  powder,  by  acidification  with  hydro- 
chloric acid  (D.  R.  P.  72942). 

IvOretin  has  been  employed,  mainly  in  the  form  of  its 
bismuth  salt,  as  an  iodoform  substitute. 

SAJODIN  (calcium iodo-behenolate)  (C22H41O2I)2Ca.  970. — 
References  D.  R.  PP.  180087, 186214, 180622, 187449, 187822. 
Five  hundred  grams  of  orucic  acid  (obtained  from  rape 
seed  oil)  are  treated  with  330  grams  of  powdered  sodium 
iodide,  and  600  c.c.  of  glacial  acetic  acid  which  has  been 
saturated  with  dry  hydrogen  chloride.  The  mixture  is 
warmed  at  40°-5o°  for  2-3  days,  with  continuous  stirring. 
It  is  then  diluted  with  water,  and  the  mono-iodo-behenolic 
acid  extracted  with  benzene.  The  benzene  solution  is 
washed,  first  with  aqueous  sulphurous  acid,  to  remove  traces 
of  iodine,  and  then  with  water,  until  the  washings  no  longer 
react  with  silver  nitrate  solution.  The  solvent  is  then 
removed  in  vacuo  at  a  low  temperature,  the  residue  con- 
sisting of  mono-iodo-behenolic  acid. 


i82         ORGANIC  MEDICINAL   CHEMICALS 

Twenty-five  parts  of  crystallised  calcium  chloride  are 
dissolved  in  120  parts  by  weight  of  hot  92  %  alcohol,  and 
the  solution  saturated  with  gaseous  ammonia.  A  further 
130  parts  of  alcohol  are  added,  after  which  the  mixture  is 
cooled.  To  it  is  added,  in  a  thin  stream,  with  good  stirring, 
a  solution  of  44  parts  of  mono-iodo-behenolic  acid  in  120 
parts  of  alcohol.  The  calcium  salt  separates  in  the  form  of 
a  thick  white  precipitate.  It  is  filtered  off  and  washed, 
first  with  alcohol,  then  with  water,  until  the  washings  are 
free  from  chloride  ;  finally  it  is  again  washed  with  alcohol 
and  dried  in  vacuo. 

Sajodin  is  a  white,  neutral,  tasteless  powder,  almost 
insoluble  in  water  and  alcohol.  It  is  stable  if  protected 
from  white  light,  under  the  influence  of  which  it  slowly 
becomes  yellow.  It  contains  about  26  %  of  iodine. 

Sajodin  is  administered  internally  in  treatment  of 
syphilis. 

TETRA-IODO-PHENOL-PHTHALEIN  (Nosophen)  . 

C(C6H2I2OH)2 

822. 


CO 

—The  preparation  of  this  compound  has  been  described  by 
Orudoff  and  Mahood  (/.  Am.  Chem.  Soc.  (1918),  40,  941), 
the  method  being  similar  to  that  given  by  the  original 
patent  specification,  D.  R.  P.  85930. 

Thirty  parts  of  phenol-phthalein  are  dissolved  in  500 
volumes  of  2N.  caustic  soda.  The  solution  is  mechanically 
stirred  and  to  it  is  added,  in  the  course  of  half  an  hour,  a 
solution  of  100  parts  of  iodine  and  120  parts  of  potassium 
iodide  in  500  parts  of  water.  The  reaction  mixture  is  stirred 
for  8  hours,  after  which  it  is  carefully  neutralised  with 
2N.  acetic  acid.  The  resulting  greyish-white  precipitate  is 
filtered  off.  It  is  redissolved  in  2  %  alkali  and  reprecipitated 
with  acetic  acid,  being  now  a  pale  yellow  colour.  After  the 
precipitate  has  been  again  dissolved  in  2  %  alkali,  the  solution 
is  strongly  acidified  with  hydrochloric  acid,  and  steam  blown 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  183 

in  until  the  precipitate  has  coagulated.  After  cooling  and 
filtration,  the  solid  is  washed  with  water  until  free  from 
chloride  and  dried  at  atmospheric  temperature.  Yield  87  %. 

It  is  purified  by  recrystallisation,  first  from  acetone  and 
then  from  a  mixture  of  acetone  and  alcohol,  from  which  it 
is  obtained  in  the  form  of  colourless  microscopic  crystals 
which  melt  at  270°-272°. 

According  to  D.  R.  P.  85930,  thirty  parts  of  phenol- 
phthalein  are  dissolved  in  100  parts  of  water  containing  40 
parts  of  caustic  soda.  At  a  temperature  not  exceeding  20° 
is  added  a  solution  of  100  parts  of  iodine  and  120  parts  of 
potassium  iodide  in  400  parts  of  water.  The  solution  is 
strongly  cooled  and  neutralised  with  hydrochloric  acid, 
when  an  amorphous  yellow-brown  precipitate  is  obtained. 
This  is  filtered  off  and  purified  by  being  dissolved  in  chloro- 
form and  reprecipitated  by  the  addition  of  ligroin. 

It  has  also  been  prepared  by  the  electrolysis  of  an 
alkaline  solution  of  phenol-phthalein  containing  the  equiva- 
lent amount  of  potassium  iodide.  Tetra-iodo-phenol  phthalein 
is  an  odourless  powder,  insoluble  in  water,  soluble  in  chloro- 
form and  in  ether. 

It  has  been  employed,  externally,  as  a  substitute  for 
iodoform,  and,  internally,  as  an  intestinal  antiseptic. 

FORMALDEHYDE  H'COH.  30.— Formaldehyde  is  usually 
prepared  as  a  solution  in  water.  Its  solution  is  variously 
termed  Formalin,  Formol,  Methanal  andlyiquor  formaldehyde. 
It  is  prepared  technically  by  the  oxidation  of  methyl  alcohol, 
derived  from  wood  spirit,  although  attempts  have  been 
made  to  obtain  it  from  methane  (D.  R.  PP.  109014,  286731) 
and  from  carbon  monoxide  (U.S.  Patent  1302016,  29/4/19). 

The  oxidation  of  methyl  alcohol  is  carried  out  by  passing 
its  vapour  mixed  with  air  over  a  catalyst  heated  at  about 
450°.    The  main  reaction  is  expressed  by  the  equation 
2CH3OH+02    ->    2HCHO+2H20+6o-4Cal. 
though  at  the  same  time  a  portion  of  the  methyl  alcohol  is 
probably  decomposed  pyrogenetically  into  formaldehyde  and 
hydrogen, 

CH3OH    ->    HCHO+H2 


184         ORGANIC  MEDICINAL  CHEMICALS 

Under  the  influence  of  high  temperature  some  of  the 
formaldehyde  is  decomposed  into  CO  and  H2,  of  which  a 
part  may  become  oxidised  to  CO2  and  water. 

The  reaction  is,  as  shown  by  the  equation,  exothermic, 
and,  once  started,  no  further  application  of  heat  is  required. 

The  conditions  which  require  to  be  observed  in  order 
that  good  yields  shall  be  obtained  have  been  worked  out  by 
OrlofI  (/.  mss.  phys.  chem.  Ges.  39,  855,  1023,  1404  (1908)  ; 
40,  796  (1909),  and  by  Le  Blanc  and  Plaschke  (Zeits.  Elektro- 
chem.  17,  55  (1911)).  The  methyl  alcohol  should  be  at  least 
90  %  in  strength  ;  100  %  being  better.  It  should  contain 
not  more  than  i  %  of  acetone.  The  highest  conversion, 
employing  a  copper  catalyst,  is  obtained  when  for  i  part  of 
methyl  alcohol  0-39  part  of  oxygen  is  taken  ;  the  smallest 
loss  of  methyl  alcohol  when  0-315  part  of  oxygen  is  employed. 
The  corresponding  figures,  using  a  silver  catalyst,  are  0-459 
and  0-314.  The  optimum  temperature  of  the  interior  of 
the  catalyst  is  450°,  this  being  regulated  by  adjustment  of 
the  rate  of  flow  of  the  methyl  alcohol-air  mixture,  or  the 
proportion  of  methyl  alcohol  contained  in  it.  The  depth  of 
the  catalyst  is  of  importance  ;  when  silver  gauze  100  mesh 
was  employed,  70  millimetres  was  found  to  be  the  best 
(le  B.  and  P.).  Using  copper,  Orloff  recommends  a  depth 
of  1 20  mm. 

The  catalytic  chamber  is  the  most  important  part  of  the 
apparatus,  and  a  brief  description  of  the  one  employed  by 
OrlofE  may  advantageously  be  given.  It  consists  of  169 
copper  tubes,  800  mm.  long,  external  diam.  19  mm.,  thick- 
ness of  wall  17  mm.,  arranged  in  circles  (1+8+16+24+32 
+40  +48)  set  in  two  copper  plates,  the  whole  being  enclosed 
in  a,  preferably  copper,  box  having  on  the  one  side  a  tube 
through  which  the  air-methyl  alcohol  mixture  is  introduced, 
on  the  other  an  exit  for  the  formaldehyde-nitrogen  vapour. 
Inside  each  tube  is  set  one  of  glass,  300  mm.  long,  internal 
diameter  14-75  mm.  Each  glass  tube  contains  a  roll  of 
copper  120  mm.  long,  made  of  gauze  of  15x15  meshes  per 
square  cm.  A  device  for  igniting  the  gases,  in  order  to  start 
the  reaction,  is  provided  and  may  consist  of  an  electrically 


i86          ORGANIC  MEDICINAL  CHEMICALS 

heated  wire.  A  catalyst  of  this  size  consumes  170  kilos  of 
methyl  alcohol  in  10  hrs.,  affording  255  kilos  of  form- 
aldehyde 38  %.  A  diagram  of  a  plant  for  the  manufacture 
of  formaldehyde  is  given  (Fig.  22). 

Air  is  compressed  by  a  pump  (i)  into  a  reservoir  (2). 
Methyl  alcohol  stored  in  (3)  flows  down  into  the  carburettor 
(4),  in  which  it  is  maintained  at  a  constant  level,  and  is 
warmed  by  means  of  a  closed  steam  coil.  Air  is  blown  into 
it  from  the  air  reservoir,  through  a  perforated  coil.  The 
temperature  is  regulated  so  that  the  ratio  of  oxygen  to 
alcohol  in  the  vapour  is  as  0-31  to  0-32  :  i.  The  mixture 
then  passes  into  the  catalyst  chamber  (5)  in  which,  after  being 
started  by  ignition,  the  reaction  proceeds  without  further 
addition  of  heat.  The  temperature  maintained  in  the  catalyst 
chamber  is  450°.  The  issuing  vapours  pass  into  the  fraction- 
ating column  (6)  in  which  38-40  %  formaldehyde  is  con- 
densed, the  methyl  alcohol  passing  over,  together  with  the 
waste  gases,  into  a  condenser  (7).  In  this  is  condensed  the 
greater  part  of  the  excess  of  methyl  alcohol,  which  runs  into 
(12),  a  store  tank  from  which  it  can  be  pumped  up  into  (3). 
The  gases,  which  still  contain  some  methyl  alcohol,  pass  into 
a  gas  scrubber  (9),  in  which  they  are  washed  with  water. 
The  washings  are  then  fractionated  in  the  fractionating 
column  (10),  the  methyl  alcohol  being  condensed  in  (n)  and 
run  into  the  store  tank  (12). 

Commercial  formaldehyde  solution  contains  35-40  %  of 
formaldehyde,  and  10-15  %  of  methyl  alcohol.  It  has  a 
specific  gravity  of  i'079~t6  I'OiS. 

The  acidity  should  not  exceed  0*23  %  w/v,  calculated 
as  formic  acid.  Heavy  metals,  sulphate  and  chloride  should 
be  absent,  and  5  c.c.  should  leave  no  weighable  residue  on 
ignition. 

Formaldehyde  solution  is  a  powerful  antiseptic,  dis- 
infectant and  deodorant.  Diluted  with  water  (50  to  100 
vols.)  it  is  used  as  a  general  antiseptic,  and  with  400-500 
vols.  as  a  mouth  wash  and  gargle. 

It  has  been  employed,  by  intravenous  injection  and  as 
an  inhalant,  in  pulmonary  phthisis. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  187 

HEXAMINE  (urotropine,  hexamethylenetetramine), 
(CH2)6N4.  140.  Also  known  as  cystamine,  aminoform, 
and  formin. 

Hexamethylenetetramine  is  produced  by  the  condensa- 
tion of  formaldehyde  and  ammonia,  in  accordance  with  the 
following  equation  : 

6HCHO+4NH4OH    ->     (CH2)6N4+ioH2O 
180  140  140  180 

Formaldehyde  solution,  containing  180  parts  of  formalde- 
hyde, e.g.  473  parts  of  a  38  %  solution,  is  treated  with  140 
parts  of  ammonium  hydrate,  for  instance,  700  parts  of  a  20% 
solution,  until  the  solution  is  slightly  alkaline,  using  rosolicacid 
as  indicator.  The  mixture  is  allowed  to  stand,  more  ammonia 
being  added  if  necessary,  for  several  hours,  until  the  alkalinity 
is  shown,  by  successive  titrations  with  N/ioo  acid,  to  remain 
constant.  The  solution  is  filtered  and  then  boiled  down  in 
an  enamelled  vessel,  preferably  under  diminished  pressure,  to 
a  thick  paste.  The  crystals  are  filtered  ofT,  by  means  of  a 
centrifugal  machine  or  vacuum  filter,  freed  from  colour  by 
washing  with  alcohol,  and  dried.  It  is  then  recrystallised 
from  water  or  alcohol  until  pure.  Hexamine  forms  colourless, 
odourless  crystals,  which  dissolve  in  rather  more  than  an  equal 
weight  of  water,  and  in  8  parts  of  90  %  alcohol.  It  does  not 
melt  on  heating,  but  sublimes  at  a  temperature  of  about  260°. 
The  aqueous  solution  should  be  perfectly  bright  and  should  be 
free  from  iron  (potassium  f errocy anide  solution) ,  heavy  metals 
(sulphuretted  hydrogen),  chlorides  or  sulphates,  ammonium 
salts  (Nessler  solution),  and  para-formaldehyde,  the  latter 
reducing  Nessler  solution  (potassium  mercuriciodide)  to 
metallic  mercury.  No  residue  should  be  left  on  ignition. 

Hexamine  is  a  urinary  antiseptic,  owing  its  action  to  the 
liberation  of  formaldehyde,  which  occurs  in  acid  fluids.  It 
is  not  so  effective,  therefore,  per  se,  if  the  urine  is  alkaline. 
Hexamine  has  been  found  to  give  excellent  results  in 
cystitis  and  typhoid  bacilluria ;  also  as  a  prophylactic 
against  the  nephritis  of  scarlatina. 

It  is  not  a  solvent  for  uric  acid. 


i88         ORGANIC  MEDICINAL  CHEMICALS 

PROFLAVINE  (3 '6  diamino-acridine  sulphate) 

CH 


NH, 


H, 


H2S04.       307- 


N 


—  The  following  reactions  are  involved  in  the  formation  of 
this  compound  :  — 

Aniline  (C6H5NH2)  -f  formaldehyde  (HCHO) 

->    anhy  dro-f  ormaldehy  de  aniline  (CH2NC6H5)  3 

(CH2NC6H5)  3  +3C6H5NH2 

-»    methylene-diphenyl-diamine 
This  compound  undergoes  rearrangement  to 


^-^-diamino-diphenyl-methane. 

Nitration     affords     NH2<^)>--CH2—  <^>NH2,     2:2 

N02  N02 

dinitro  4  :  4  diamino-diphenyl-methane,  which,  on  reduction 
and  heating,  yields  3  '6  diamino-hydro-acridiae 


NH2    NH2 

which  readily  changes  to  3-6  diamino-acridine  —  "  proflavine." 
Aniline,  93  parts  (i  mol.),  is  dissolved  in  5  volumes  of 
96  %  alcohol  (S.V.M.)  and  the  solution  cooled  and  stirred 
whilst  120  parts  of  40  %  formaldehyde  solution  (i  mol.) 
are  gradually  added.  After  the  addition  is  completed, 
stirring  is  continued  until  the  odour  of  formaldehyde  has 
disappeared,  when  a  second  molecular  portion  of  aniline, 
93  parts,  is  added.  The  mixture  is  boiled,  using  a  reflux 
condenser,  for  2  hours,  to  complete  the  formation  of  methy- 
lene-diphenyl-diamine. 

Aniline  hydrochloride  (i  mol.),  130  parts,  is  then  added, 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  189 

and  boiling  continued  for  a  further  12  hours.  The  alcohol 
is  distilled  off,  the  residue  made  alkaline  with  caustic  soda 
and  the  excess  of  aniline  removed  by  distillation  with 
(superheated)  steam.  The  residual  oil,  which  consists  of 
^-^-diamino-diphenyl-methane,  is  then  purified  by  solution 
in  dilute  hydrochloric  acid  and  reprecipitation  with  dilute 
alkali.  The  base  is  filtered  off,  washed  and  dried. 

The  nitration,  reduction  and  conversion  are  carried  out, 
according  to  D.  R.  P.  230412,  in  the  following  manner  : 
Twenty -five  kilos  of  ^-^-diamino-diphenyl-methane  are  dis- 
solved in  500  kilos  of  sulphuric  acid  (66°  Be.),  cooled  to  o° 
and  nitrated  with  54  kilos  of  a  mixture  of  sulphuric  and 
nitric  acids  containing  16  kilos  of  HNO3  (100  %),  the  temper- 
ature being  kept  below  5°.  The  whole  is  allowed  to  stand 
for  a  further  2  to  3  hours,  at  8°-io°,  then  run  out  on  to  ice, 
and  neutralised  with  caustic  soda  liquor.  Ammonia  solution 
is  added,  to  precipitate  the  base,  which  is  centrifuged  and 
washed  with  water.  The  product,  without  being  dried,  is 
dissolved  in  24  kilos  of  hydrochloric  acid  (sp.gr.  i'i8)  and 
heated  to  50°,  when  54  kilos  of  granulated  tin  are  added. 
A  vigorous  reaction  ensues,  the  temperature  rising  to  110°. 
The  resulting  solution  is  transferred  to  an  autoclave  and 
heated  to  135°  for  4  hours.  After  cooling,  the  resulting 
crystalline  tin  double  compound  of  3*6  diamino-acridine  is 
dissolved  in  500  litres  of  boiling  water,  the  solution  neutralised 
with  caustic  soda  and  then  made  alkaline  with  sodium 
carbonate  solution.  After  cooling,  the  precipitate,  which 
consists  of  tin  oxide  and  diamino-acridine,  is  filtered  off  and 
the  latter  compound  removed  by  repeated  extractions  with 
boiling  water,  from  which  it  crystallises  on  cooling  in  shining 
orange  to  brown-coloured  leaflets.  The  product  is  filtered 
off  and  either  dried  and  used  for  the  manufacture  of  acri- 
flavine  or  converted  into  proflavine  sulphate,  which  is 
effected  by  dissolving  in  a  slight  excess  of  hot  dilute  sulphuric 
acid  and  allowing  to  crystallise. 

Proflavine  sulphate  separates  in  dark  red  or  reddish- 
brown  crystals,  which  dissolve  in  about  100  parts  of  cold 
water. 


igo         ORGANIC  MEDICINAL   CHEMICALS 

A  solution  which  remains  perfectly  bright  for  24  hours 
should  be  afforded  in  500  parts  of  normal  saline  solution 
(0-9  %  NaCl).  Tin  and  other  metals  should  be  absent,  and 
a  sample  of  0-5  gram  should  afford  no  weighable  ash  on 
ignition  in  air. 

Proflavine  sulphate  is  a  valuable  germicide  and  anti- 
septic. It  is  employed  in  the  form  of  a  0*1  %  or  0-2  % 
solution,  and  as  an  ointment.  A  wide  employment  in  the 
treatment  of  surface  wounds  was  attained  during  the  war, 
and  an  increasingly  extensive  use  for  it  is  being  found  in  the 
treatment  of  gonorrhoea,  by  urethral  or  vaginal  injection. 

ACRIFLAVINE  (2-6  diamino-acridinium  metho-chloride) 

CH 


NH2\/\  A/NH2'HC1.      296. 


CH3  Cl 

— Acriflavine  is  prepared,  according  to  D.  R.  P.  243085,  in 
the  following  manner.  Five  kilos  of  3-6  diamino-acridine 
(see  proflavine,  p.  188)  are  acetylated  by  boiling  with 
13  kilos  of  acetic  anhydride  and  1-25  kilos  of  anhydrous 
sodium  acetate,  until  no  diazo  reaction  is  given  by  a 
test  sample.  Thirty -five  litres  of  water  are  added  and  the 
solution  boiled,  filtered,  and  allowed  to  crystallise.  The 
crystals  are  filtered  off,  dissolved  in  hot  water,  and  treated 
with  8  litres  of  ammonia  solution.  The  3-6  diacetyl-diamino 
acridine  is  filtered  off  when  cold,  washed  and  dried. 

Four  kilos  of  the  acetyl  compound  are  dissolved  in  40  kilos 
of  nitro-benzol,  at  180°.  At  a  slightly  lower  temperature, 
i.e.  175°,  3*3  kilos  of  methyl  ^-toluenesulphonate  are  added 
and,  after  cooling,  the  separated  crystals  are  filtered  off. 
They  consist  of  the  methyl  toluene-sulphonate  compound 

CHCOaNHl   A    I  JNHCQCBi 


CH3   S02C6H4CH3 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  191 

5-45  kilos  of  this  are  boiled  for  several  hours  with  a 
mixture  of  17*5  litres  of  concentrated  hydrochloric  acid  and 
j-7'5  litres  of  water.  On  cooling,  the  hydrochloride  of  3*6 
diamino-acridinium  metho-chloride,  "  acriflavine/'  crystal- 
lises out  and  is  filtered  off  and  dried. 

Acriflavine  crystallises  in  dark  red  shining  crystals, 
which  dissolve  in  5  parts  of  cold  water. 

A  0*2  %  solution  in  normal  saline  should  be  perfectly 
clear  after  24  hours.  Proflavine  should  be  absent,  as 
indicated  by  100  c.c.  of  a  0*4  %  solution  remaining  un- 
clouded for  10  minutes  upon  addition  of  10  c.c.  of  N.  caustic 
soda  solution. 

Tin  and  other  heavy  metals  must  be  undetectable,  and 
no  weighable  residue  must  be  left  after  ignition  in  air  of 
0*5  gram. 

Acriflavine  is  employed  in  the  same  concentration  and 
for  the  same  purposes  as  proflavine,  to  which  it  has  a  similar 
action. 

MALACHITE  GREEN 

~>(CH3)2C1 

364'4- 

N(CH3)2 

—The  following  account  of  the  preparation  of  this  substance 
is  taken  from  Cain  and  Thorpe's  Synthetic  Dyestuffs,  p.  270. 
Thirty-five  grams  of  dimethylaniline  and  14  grams  of 
benzaldehyde  are  mixed  with  31*5  grams  of  concentrated 
hydrochloric  acid  and  the  mixture  heated,  under  a  reflux 
condenser,  for  24  hours,  at  100°.  The  mass  is  made 
alkaline  with  caustic  soda,  after  which  traces  of  benzaldehyde 
and  of  dimethylaniline  are  removed  by  a  current  of  steam. 
On  pouring  into  i  litre  of  water  the  leuco  base  separates  in 
the  form  of  hard  granules.  It  is  filtered  off,  washed  free 
from  alkali,  and  an  estimation  made  of  the  moisture  content. 
It  is  oxidised  as  follows  :  Ten  grams  of  leuco  base  (dry 
weight)  are  melted  by  a  current  of  steam.  Hydrochloric 
acid,  containing  27  grams  of  HC1,  and  4  grams  of  acetic 
acid  in  2\  to  3  litres  of  water  are  added,  and  a  thin  paste 


192         ORGANIC  MEDICINAL  CHEMICALS 

containing  7*5  grams  of  pure  lead  peroxide  is  allowed  to 
flow  in,  with  stirring,  which  is  continued  for  2  hours  after 
the  addition  is  complete.  Unchanged  lead  peroxide  is  then 
filtered  off ;  the  filtrate  is  heated  to  boiling  point  and 
treated  with  sodium  sulphate,  to  remove  the  lead.  After 
filtration  the  solution  is  again  raised  to  boiling  point  and  the 
base  is  precipitated  with  caustic  soda  solution.  After 
cooling,  it  is  filtered  off,  washed,  dried,  and  purified  by  being 
dissolved  in  light  petroleum  and  filtered  from  impurities, 
after  which  the  petrol  is  distilled  off  by  means  of  a  current 
of  steam. 

The  hydrochloride  has  been  employed  as  an  antiseptic, 
in  the  treatment  of  wounds. 

N 


CHINOSOL  (8-hydroxyquinoline  sulphate) 

\/X/ 

388. — Chinosol  was  originally  supposed  to  be  potassium  ortho- 
hydroxyquinoline  sulphonate,  but  was  subsequently  found, 
when  prepared  according  to  the  patent  specifications  D.R.  P. 
88520  and  E.  P.  1409/1896,  to  be  a  mixture  of  8-hydroxy- 
quinoline sulphate  and  potassium  sulphate. 

Ortho-hydroxyquinoline  is  made  by  gently  boiling,  for  3-4 
hours,  a  mixture  of  7  parts  of  ortho-nitrophenol,  15  parts 
of  ortho-aminophenol  hydrochloride,  25  parts  of  glycerine 
and  20  parts  of  sulphuric  acid.  The  reaction  mixture  is 
diluted  with  water,  made  alkaline,  and  the  ortho-oxyquino- 
line  distilled  over  in  steam  (Skraup,  Ber.  1 6,  713).  M.p.  73°- 

74°. 

According  to  D.  R.  P.  88520,  E.  P.  1409/1896,  twenty- 
nine  kilos  of  ortho-oxyquinoline  are  dissolved  in  120 
kilos  of  alcohol.  To  the  solution  are  gradually  added, 
with  good  stirring,  25  kilos  of  finely-powdered  potassium 
pyrosulphate.  The  mixture  is  boiled  for  10  hours,  employing 
a  reflux  condenser,  and,  after  cooling,  the  product,  chinosol, 
is  filtered  off. 

This  was  believed,  as  stated  above,  to  consist  of  the 
potassium  salt  of  an  oxyquinoline  sulphonic  acid,  but  was 
proved  subsequently  to  be  a  mixture  of  the  neutral  sulphate 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  193 

and  potassium  sulphate.  For  preparing  the  neutral  sulphate 
in  a  pure  state,  the  following  method  was  patented  (D.  R.  P. 
l87943  ;  B.  P.  11725/1906)  : 

To  a  solution  of  29  parts  of  o-oxyquinoline  in  100  parts 
of  96  %  alcohol  are  added  I0'6  parts  of  sulphuric  acid 
(65-5°  Be.).  The  neutral  sulphate  separates,  is  filtered  off 
and  dried  at  a  low  temperature. 

Prepared  by  this  method  chinosol  is  a  yellowish  crystalline 
powder.  M.p.  I75°-I77°.  It  is  very  soluble  in  water, 
sparingly  soluble  in  alcohol,  and  insoluble  in  ether. 

Chinosol  is  a  powerful  antiseptic,  and  is  claimed  to  be 
stronger  in  this  respect  than  mercuric  chloride,  but  is  only 
a  relatively  feeble  germicide,  its  great  value  being  due  to 
its  strong  inhibiting  action  on  the  growth  of  bacteria.  It 
possesses  marked  analgesic  power,  but  should  be  diluted 
down  when  used  in  the  form  of  powder,  as  otherwise  local 
irritation  and  swelling  may  ensue.  Chinosol  is  non-toxic, 
does  not  coagulate  albumen  or  injure  mucous  tissues. 


TANNIC  ACID  DERIVATIVES 

Several  tannic  acid  derivatives  are  employed  as  intestinal 
antiseptics.  Because  the  acid  itself  is  irritating  to  the 
stomach,  and  is  to  a  large  extent  decomposed  or  absorbed 
before  reaching  the  intestine,  efforts  have  been  made  to 
produce  combinations  of  it  with  other  substances,  to  render 
it  non-irritating  to  the  stomach ;  which  combinations  become 
broken  up  in  the  intestines,  so  that  the  astringent  effect  of  the 
tannic  acid  is  exerted  where  required. 

TANNALBEN  (albumen  tannate). — Tannalben  is  a  com- 
pound of  tannic  acid  and  egg  albumen.  It  is  prepared  by 
mixing  10  parts  of  a  10  %  aqueous  solution  of  egg  albumen 
with  6-5  parts  of  a  10  %  aqueous  solution  of  tannic  acid. 

The  precipitate  which  is  formed  is  separated  by  filtration, 
washed  with  water  until  the  washings  react  only  faintly 
with  ferric  chloride  solution,  dried  and  powdered,  and  heated 
at  126°  for  6  hours  (B.  PP.  6140  and  13281  of  1896). 
!•  13 


194         ORGANIC  MEDICINAL  CHEMICALS 

Tannalben  is  a  light-brown,  odourless  and  tasteless 
powder,  containing  about  50  %  of  tannic  acid.  It  is 
practically  insoluble  in  water  and  in  alcohol,  but  dissolves 
gradually  in  alkaline  fluids,  which  resolve  it  into  its 
constituents. 

One  gram  of  tannalben,  digested  for  4  hours  at  40° 
with  o-i  gram  of  pepsin,  50  c.c.  of  water,  and  1-5  grams  of 
dilute  hydrochloric  acid  (12*5  %),  leaves  a  residue  which, 
after  washing  with  30  c.c.  of  water  and  drying  at  100°, 
should  weigh  not  more  than  0*5  gram. 

Tannalben  is  employed  as  an  intestinal  astringent.  It  is 
unaffected  by  gastric  secretions  but  is  digested  by  the 
pancreatic  fluids.  It  is  useful  in  diarrhoea,  especially  in  that 
of  children,  and  in  phthisis. 

TANNOFORM  (methylene  ditannin)  (CuHgOg^CH^.  656. 
— Tannoform,  as  its  name  indicates,  is  a  compound  derived 
from  tannic  acid  and  formaldehyde. 

Five  kilos  of  tannin  are  dissolved  (D.  R.  P.  88082)  in  hot 
water,  10  kgs.  of  30  %  formaldehyde  are  then  added,  followed 
by  concentrated  hydrochloric  acid  so  long  as  a  precipitate  is 
produced. 

This  is  filtered  off  by  means  of  a  filter  press,  washed  well 
with  cold  water,  and  dried  at  a  moderate  temperature. 

The  same  substance  is  stated  (D.  R.  P.  93593)  to  be 
obtained  by  heating  tannin  and  formaldehyde  together  for 
several  hours  in  an  autoclave,  at  100°. 

Tannoform  is  a  voluminous  reddish  powder,  odourless, 
tasteless.  It  is  insoluble  in  water,  but  dissolves  in  alcohol 
and  in  alkaline  liquids.  It  is  used  externally  in  skin  diseases, 
such  as  eczema,  and  as  an  application  to  wounds.  Internally, 
it  is  administered  in  chronic  intestinal  catarrh. 

Other  derivatives  of  tannic  acid  used  for  the  same 
purposes  are :  Diacetyl-tannin  or  Tannigen  CuH8O9(COCH3)2, 
and  Tannocol,  a  combination  of  tannic  acid  with  gelatine. 


ORGANIC  ANTISEPTICS  AND  DISINFECTANTS  195 


SANTALOI,  AND  ITS  DERIVATIVES 

Sandalwood  oil  is  obtained  by  steam  distillation  under 
pressure  from  the  wood  of  Santalum  album,  I,.,  in  which  it 
is  present  to  the  extent  of  2*5  to  6*0  %. 

The  Bast  Indian  oil  only  is  official  in  the  British  Pharma- 
copoeia. It  is  a  pale-yellow,  oily  liquid,  having  a  characteristic 
odour  and  possessing  a  specific  gravity  of  0*975  to  0*980  ;  it 
is  required  to  form  a  clear  solution  in  six  times  its  volume 
of  70  %  alcohol. 

The  oil  is  lavo-rotatory  and  has  an  optical  rotation  of 
— 16°  to  —20°  in  a  tube  of  100  mm.  length.  Not  less  than 
90  %  of  alcohols,  calculated  in  terms  of  santalol,  should  be 
present.  This  is  determined  by  acetylating  a  portion  of  the 
oil  and  determining  the  saponification  value  of  the  acetylated 
product. 

Sandalwood  oil  is  employed  extensively  in  gonorrhoea ; 
it  is  a  stimulating  disinfectant  to  the  mucous  membranes  of 
the  bladder  and  urethra. 

SANTALOL  (articol)  Ci5H23OH.  220. — For  the  prepa- 
ration of  santalol,  6  kilos  of  Sandalwood  oil  are  saponified 
by  boiling  for  2-3  hours  with  0*6  kilo  of  potassium  hydroxide 
in  2  kilos  of  90  %  alcohol.  The  solvent  is  then  removed  by 
distillation  and  the  santalol  distilled  over  in  a  current  of 
superheated  steam.  The  first  portion  of  the  distillate  is 
set  aside  if  it  possesses  an  objectionable  odour,  and  added  to 
the  following  batch.  Yield,  75-80  %  of  the  weight  of  oil 
taken.  (D.  R.  PP.  110485,  116815.) 

Santalol  is  an  effective  urinary  antiseptic  and  is  stated 
not  to  cause  disturbance  of  the  stomach  and  kidneys, 
whereas  Sandalwood  oil  may  do  so  at  times.  It  is  employed 
in  gonorrhoea  and  cystitis. 

On  account  of  the  unmistakable  and  unforgettable  odour 
of  sandalwood  oil  and  santalol,  which  has  become  universally 
associated  with  the  disease  gonorrhoea,  odourless  derivatives 
of  santalol  have  been  a  practical  requirement  and  several 
of  these  have  been  introduced  into  medicine. 


196         ORGANIC  MEDICINAL  CHEMICALS 

SANTALOL  CARBONATE  (D.  R.  P.  187254)  (Ci5H23O)2CO. 
466. — Two  hundred  parts  of  sandalwood  oil  are  treated 
with  100  parts  of  phenyl  carbonate  and  2  parts  of  powdered 
caustic  soda,  and  the  mixture  heated  under  reduced  pressure. 
At  140°  separation  of  phenol  commences  and  is  completed 
at  175°.  The  residue,  which  consists  of  almost  pure  santalol 
carbonate,  is  washed  with  water,  and  can  be  purified  by 
distillation  in  steam. 

2C15H23OH+(C6H50)2CO    -»     (C15H230)2CO+2C6H5OH 

Santalol  carbonate  is  a  yellow,  oily  liquid,  almost  tasteless 
and  odourless. 

It  is  broken  up  in  the  intestine  into  santalol  and  has 
therefore  the  same  antiseptic  action  as  the  latter. 

ALLOSAN  (santalyl  allophanate)  Ci5H23OCONHCONH2. 
306.  (D.  R.  P.  204922).— To  a  solution  of  1-59  kilos  of 
carbamic  chloride  (2  mols.)  in  n  kilos  of  benzol,  are  added 
2 '2  kilos  of  santalol,  with  efficient  stirring  and  good  cooling. 
After  several  hours'  standing,  the  benzol  is  removed  by 
distillation,  the  product  washed  with  petroleum  and 
recrystallised  from  a  mixture  of  benzol  and  petroleum. 

C15H23OH+C1CONH2    ->    C15H23OCONH2-fHCl 

Santalyl  carbamate. 

C15H23OCONH2+ClCONH2->Ci5H23OCONH-CO-NH2+HCl 

Six  kilos  of  the  benzol  employed  in  the  above  example 
may  be  replaced  with  advantage  by  2*5  kilos  of  dimethyl- 
aniline,  which  combines  with  the  hydrogen  chloride 
formed  by  the  reaction.  The  mixture,  after  standing  for 
several  hours,  is  filtered,  and  the  filtrate  washed  with  dilute 
sulphuric  or  hydrochloric  acid,  to  remove  any  remaining 
dimethylaniline,  after  which  the  solvent  is  distilled  off,  and 
the  product  purified  as  before. 

Allosan  forms  white  crystals  which  are  tasteless.  It  is 
soluble  in  organic  solvents,  insoluble  in  water. 


SECTION  VI.— PURGATIVES 

ALMOST  any  drug  which  acts  as  a  skin  irritant  will  cause 
evacuation  of  the  bowel,  but  in  the  medicinal  sense  a  purga- 
tive is  an  irritant  which  acts  only  upon  the  intestine.  The 
substances  employed  in  medicine  are  for  the  most  part 
crude  vegetable  products.  Even  in  those  cases  in  which 
the  chief  active  principle  can  be  separated,  preference  is 
generally  given  to  the  cruder  total  extract  or  resin  because 
more  satisfactory  action  is  obtained  from  it. 

The  principal  chemical  investigations  that  have  been 
made  in  this  connection  concern  the  anthraquinone  deriva- 
tives. Aloes,  cascara,  rhubarb  and  senna  each  contain 
hydroxy-methyl-anthraquinones.  The  glucosides  of  emodin 
and  chrysophanic  acid  are  purgatives  ;  the  probable  formulse 
of  these  two  anthraquinone  derivatives  are  as  follows  : — 

CH30    OH  CH30    OH 

^ 


\6/    ^*~^   \4X 

O     OH  O     OH 

Emodin.  Chrysophanic  acid. 

An  investigation  of  the  synthetic  homologous  tri-hydroxy 
anthraquinones  has  shown  that  the  position  of  the  hydroxy 
groups  considerably  affects  the  activity.  Anthrapurpurin, 
1.2.7  trihydroxy-anthraquinone,  was  found  to  be  more 
active  than  the  1.2.6,  this  more  active  than  the  1.2.3,  and 
this  more  so  than  the  1.2.4.  The  tetra-hydroxy  and 
hexahydroxy-anthraquinones  were  found  less  active  than  the 
1.2.3  tri-hydroxy  derivative.  The  presence  of  methyl 
groups  appears  to  have  a  very  uncertain  influence. 

Phenol-phthalein  is  the  only  synthetic  purgative  which  is 


198         ORGANIC  MEDICINAL  CHEMICALS 

in  practical  use  on  a  large  scale  ;  the  discovery  of  its  physio- 
logical action  was  accidental. 

The  ideal  purgative  has  yet  to  be  found,  there  being 
great  need  of  research  of  this  kind 

ALOIN  (barbaloin)  C16H18O7'3H2O.  376.— Aloin,  or 
barbaloin,  is  a  derivative  of  tetra-hydroxy-methyl-anthra- 
quinone,  and  according  to  Robinson  and  Simonsen  (T.  Chem. 
Soc.  (1909),  95,  1087),  may  probably  be  represented  by  the 
formula  : — 

CO-0-CH2 


OH 

It  yields  on  oxidation  aloe-emodin,  a  tri-hydroxy-methyl 
anthraquinone,  showing  its  near  relationship  to  emodin 
derived  from  rhubarb  and  to  chrysophanic  acid  derived 
from  araroba. 

Aloin  is  prepared  from  Cura^oa  or  Barbadoes  aloes, 
the  desiccated  juice  of  the  leaves  of  Aloe  vera,  I/.,  and 
Aloe  chinensis,  Steud.  Cura£oa  aloes  varies  considerably 
in  colour  and  consistency,  from  a  stiff  yellowish- 
brown  paste  to  a  deep  brown  or  almost  black,  hard  solid. 
It  has  a  comparatively  smooth  surface  when  fractured. 
Several  tests  can  be  applied  in  order  to  distinguish  the 
Barbadoes  from  the  African  (Natal  or  Cape)  aloes,  which  do 
not  yield  an  aloin  of  the  same  composition.  These  other 
aloins  are  named  respectively  Socaloin,  Nataloin  and 
Capaloin. 

If  a  particle  of  Barbadoes  aloes  be  treated  with  concen- 
trated nitric  acid  a  red  colour  should  be  produced,  which 
changes  to  green.  Cape  aloes  gives  a  green  colour,  whilst 
Natal  aloes  affords  a  permanent  crimson  colour. 

No  blue  colouration  should  be  produced  when  the  vapour 
of  nitric  acid  is  blown  over  powdered  aloes  which  has  been 
previously  moistened  with  sulphuric  acid. 


PURGATIVES  199 

Not  less  than  70  %  of  the  aloes  should  be  soluble  in  water 
and  it  should  dissolve  almost  completely  in  a  mixture  of 
90  %  alcohol  with  one  half  its  volume  of  water. 

On  ignition  the  quantity  of  ash  should  not  exceed  3*0  %. 

For  the  preparation  of  aloin  powdered  Barbadoes  aloes 
is  dissolved  in  9  to  10  times  its  weight  of  boiling  water.  The 
solution  is  acidified  with  sulphuric  acid,  allowed  to  cool 
and  filtered  from  resinous  matter.  The  bright  filtrate  is 
neutralised  and  evaporated  down  in  vacuo  (Fig.  23)  until 
it  has  a  volume  of  about  one  gallon  for  each  five  pounds  of 
aloes  taken.  It  is  then  allowed  to  cool,  a  few  crystals  of 
aloin  are  added  and  it  is  allowed  to  stand.  When  crystal- 
lisation is  completed,  the  crystals  which  have  separated  are 
filtered  off,  and  washed  with  a  small  quantity  of  diluted 
alcohol.  They  are  recrystallised  from  dilute  ethyl  alcohol, 
or  from  methyl  alcohol.  The  yield  is,  according  to  the 
quality,  10  to  20  per  cent,  of  the  weight  of  aloes  taken. 

Barbaloin  is  a  bright  yellow  crystalline  powder  possessing 
a  bitter  taste.  It  dissolves  in  120  parts  of  cold  water  and 
in  1 8  parts  of  90  %  alcohol.  In  hot  water  and  alcohol  it  is 
readily  soluble.  The  solutions  are  neutral.  After  dehydra- 
tion at  100°  barbaloin  melts  at  147°. 

Cold  nitric  acid  (sp.  gr.  1-42)  gives  a  cherry-red  colouration 
(distinction  from  Socaloin,  Nataloin,  and  Capaloin).  Copper 
sulphate  gives  a  bright  yellow  colour  with  a  dilute  aqueous 
solution  ;  this  when  mixed  with  a  few  drops  of  a  con- 
centrated solution  of  sodium  chloride  gives  a  red  colour, 
and  on  adding  a  little  alcohol  the  colour  becomes  violet 
(distinction  from  Nat-  and  Cap-aloin). 

Absence  of  emodin  is  shown  by  shaking  a  quantity  of 
aloin  with  benzene  (10  vols.),  when  the  benzene  solution 
should  not  impart  more  than  a  faint  pink  colour  to  an  equal 
volume  of  5  %  ammonia  when  shaken  with  it.  Aloin  is  a 
bitter  tonic,  and  purgative,  acting  chiefly  on  the  large 
intestine.  It  is  a  good  tonic  cathartic  in  habitual  constipa- 
tion and  in  that  associated  with  ansemia  and  amenorrhcea. 
Administered  by  an  enema  it  is  a  vermifuge.  It  is  also  an 
emmenagogue. 


200         ORGANIC  MEDICINAL  CHEMICALS 

CASCARA  SAGRADA. — Cascara  Sagrada  is  the  name  given 
to  the  dried  barks  of  Rhamnus  purshiana,  R.  frangula,  and 


FIG.  23. — Vacuum  still  for  concentration  of  extracts. 

R.   Calif ornicus.    It  is  a  valuable  tonic  laxative,   acting 
principally  on  the  large  intestine.     It  is  especially  useful  in 


PURGATIVES  201 

obstinate  and  habitual  constipation,  for  which  it  is  given, 
usually  in  the  form  of  extract  in  pills,  or  as  a  fluid  preparation, 
in  such  a  continuous  manner  that  a  normal  condition  is 
gradually  brought  about. 

Extract  of  Cascara  Sagrada.— The  bark,  in  No.  20 
powder,  is  exhausted  by  percolation  with  distilled  water,  and 
the  extract  evaporated  to  dry  ness  in  vacuo. 

Liquid  Extract  of  Cascara. — Five  parts  of  cascarabark 
are  exhausted  by  percolation  with  distilled  water  and  the 
percolate  evaporated  to  3  parts  ;  one  part  of  alcohol  (90  %) 
mixed  with  an  equal  weight  of  distilled  water  is  added,  the 
whole  being  made  up  to  5  parts  by  the  addition,  if  necessary, 
of  more  water.  Isolation,  in  a  pure  state,  of  the  constituent 
or  constituents  to  which  the  physiological  activity  of  the  drug 
is  due  has  not  yet  been  effected,  but  anthraquinone  derivatives 
allied  to  emodin  are  known  to  be  present.  An  exhaustive 
chemical  examination  of  the  constituents  of  cascara  extract 
was  made  by  Jowett,  and  presented  in  a  paper  to  the 
American  Pharmaceutical  Association,  1904.  The  active 
principle  was  found  to  be  contained  almost  exclusively  in  an 
ethyl  acetate  solution  of  that  portion  of  a  water  extract 
that  is  precipitated  by  lead  sub-acetate,  but  all  attempts  to 
obtain  a  pure  substance  from  it  were  unsuccessful. 

This  active  extract  was  obtained  in  the  following  way. 
The  powdered  bark  was  exhausted  thoroughly  with  hot 
alcohol,  and  the  solvent  removed  by  distillation.  The  dried 
.extract  was  mixed  with  water,  and  filtered  from  fatty  matter. 
The  filtrate  was  extracted  with  chloroform,  which  removed 
emodin  and  an  isomeride,  treated  with  lead  acetate  solution 
and  filtered  from,  the  resulting  precipitate.  L,ead  subacetate 
solution  was  added  to  the  filtrate,  and  the  bulky  red  sub- 
stance, which  was  precipitated,  collected,  and  washed  well 
with  water.  It  was  then  suspended  in  water  and  decomposed 
with  sulphuretted  hydrogen.  The  filtrate  from  the  lead 
sulphide  was  concentrated  as  far  as  possible  by  evaporation 
in  a  vacuum.  The  syrupy  residue  was  mixed  with  sawdust, 
dried,  and  extracted  with  hot  ethyl  acetate.  On  removing 
the  solvent  a  dark-red  residue  was  obtained,  and  this  was 


202         ORGANIC  MEDICINAL  CHEMICALS 

found  by  physiological  tests  to  contain  the  active  properties 
of  the  drug. 

RHUBARB. — The  official  rhubarb  "  root  "  consists  of 
the  erect  rhizomes  of  Rheum  palmatum,  I^inn.,  Rheum 
officinale,  Baill.,  and  probably  other  species,  and  is  obtained 
from  China  and  Thibet.  The  best  root  is  derived  from  the 
province  of  Shensi.  It  is  dried  in  the  sun.  The  English 
cultivated  rhubarb,  R.  officinale,  is  less  active  as  a  purgative. 

Rhubarb  is  cathartic  and  astringent,  the  purgative  effect 
preceding  the  astringent,  so  that  its  use  is  indicated  in 
diarrhoea  when  an  aperient  is  needed.  In  small  doses  it  is 
a  stomachic  tonic.  It  is  non-irritant  and  is  suitable  for 
increasing  the  effect  of  other  cholagogues  and  cathartics. 

In  pharmacy  several  extracts  are  employed.  Extract 
of  Rhubarb  is  a  dried  extract  made  by  exhausting  the  drug 
with  60  %  alcohol,  and  concentrating  the  extract  to  dry  ness. 

Infusion  of  Rhubarb  is  made  by  infusing  i  part  of 
rhubarb,  cut  into  thin  slices,  with  20  parts  of  distilled  water 
for  15  minutes. 

Concentrated  Solution  of  Rhubarb.— Ten  parts  of 
rhubarb  root  are  percolated  with  20  %  alcohol  to  yield  20 
parts. 

A  recent  investigation  of  the  constituents  of  rhubarb  root 
has  been  made  by  Tutin  and  Clewer  (T.  Chem.  Soc.  (1911), 
99,  946).  Three  constituents  only  were  found  which  possess 
a  purgative  action :  aloe-emodin,  hydroxy-methyl  dihydroxy- 
anthraquinone  C14H5O2(OH)2'CH2OH,  present  to  the  extent 
of  0-16  % ;  chrysophanic  acid,  dihydroxy-methyl-anthra- 
quinone  CH3-Ci4H5O2(OH)2,  (0-49  %),  both  of  which  are 
distinctly  purgative,  though  not  very  active  ;  and  a  non- 
glucosidic  resin  (10-4  %),  which  appears  to  be  the  chief 
purgative  principle. 

o-i  gram  of  this  possessed  a  much  more  pronounced 
purgative  action  than  the  same  weight  of  aloe-emodin  or  of 
chrysophanic  acid,  although  it  represented  a  much  smaller 
weight  of  the  drug.  This  resin  was  obtained  in  the  following 
manner  :  the  drug  was  exhausted  with  hot  alcohol,  and  the 
extract  freed  from  solvent  and  boiled  out  with  water.  The 


PURGATIVES  203 

aqueous  portion  was  extracted  first  with  ether,  whereby 
cinnamic  acid,  rhein,  emodin  methyl-ether,  and  chryoso- 
phanic  acid  emodin,  aloe-emodin,  etc.,  were  removed,  and 
then  with  amyl  alcohol.  The  first  amyl  alcoholic  extract 
was  deprived  of  solvent  by  evaporation  under  reduced 
pressure,  the  residue  dissolved  in  alcohol  and  the  solution 
mixed  with  an  equal  volume  of  chloroform.  A  dark- 
coloured  resin  was  precipitated,  which,  as  described  above, 
was  found  to  be  the  main  active  principle  of  rhubarb. 
EXODIN  (diacetyl-rufigallic  acid  tetra-methyl  ester) 

C12H2(CO)2(OCH3)4(OCOCH3)2 
Rufigallic  acid,  hexa-hydroxy-anthraquinone 

OH  CO 


CO  OH 

is  produced  by  heating  gallic  acid  with  sulphuric  acid 
(Ann.  19,  204).  Methylation  is  brought  about  (Ber. 
IO,  885)  by  heating  with  excess  of  methyl  iodide  in  the 
presence  of  4  equivalents  of  caustic  potash  in  aqueous 
methyl  alcoholic  solution,  for  3-4  hours  at  120°- 
130°  under  pressure.  A  red,  insoluble,  powdery  mass  is 
obtained,  and  after  being  filtered  off  is  recrystallised  from 
ethyl  acetate,  from  which  it  separates  in  shining  gold  leaflets. 
This  substance  is  tetra-methoxy-dihydroxy-anthraquinone 
C12H2(CO)2(OH)2(OCH3)4.  It  is  insoluble  in  ether  and  water, 
dissolves  with  difficulty  in  boiling  alcohol  ;  is  easily  soluble 
in  acetic  acid  and  ethyl  acetate. 

The  acetylation  is  carried  out  as  follows  :  —  Five  kilos 
of  the  above  product  are  boiled  for  f  hour,  under  a  reflux 
condenser,  with  20  kilos  of  glacial  acetic  acid  and  1*25  kilos 
of  powdered  anhydrous  sodium  acetate.  After  being  cooled 
to  6o°-8o°  the  reaction  mixture  is  poured  into  18  kilos  of 
water  and  left  to  stand  for  a  day  or  two.  The  crystalline 
diacetyl  compound  which  separates  is  filtered  off  and  re- 
cry  siallised,  from  alcohol,  benzene,  or  acetic  acid  (D.  R.  P. 
151724).  M.p.  i8o°-i90°.  It  is  stated  to  be  a  mild  laxative 


204         ORGANIC  MEDICINAL  CHEMICALS 

CHRYSAROBIN. — Chrysarobin  is  the  name  given  to  the 
crystalline  residue  which  results  from  the  extraction  of  Goa 
powder.  Goa  powder  or  araroba  is  a  concretion  found  in 
cavities  in  the  tree  trunk  of  Andira  araroba.  It  is  imported 
from  Brazil.  For  the  preparation  of  chrysarobin,  the 
powdered  material  is  extracted  with  hot  benzene  or  hot 
chloroform  and  the  extract  dried.  A  yield  of  upwards  of 
50  per  cent,  is  to  be  expected  from  a  Goa  powder  of  satis- 
factory quality.  It  consists  of  a  mixture  of  chrysophanic 
acid  (dihydroxy-methyl-anthraquinone)  and  its  ethers.  It 
is  a  crystalline  yellow  powder,  soluble  in  chloroform  and 
benzene  and  partially  dissolved  by  alcohol  and  by  ether. 

It  is  chiefly  used  as  a  parasiticide  and  is  employed  in 
ointments  for  ringworm,  acne,  psoriasis,  alopoecia,  etc. 

SENNA. — The  leaves  and  fruits  of  Cassia  acutifolia 
(Alexandrian  senna)  and  of  Cassia  angustifolia  (Tinnevelly 
or  Bast  Indian  senna)  have  an  extremely  high  value  as 
laxatives.  The  active  principles  have  not  been  completely 
identified,  but  rhein  and  aloe-emodin  have  been  found.  It 
therefore  probably  owes  its  activity  to  anthraquinone 
derivatives.  Its  activity  is  more  readily  destroyed  than  that 
of  rhubarb  or  cascara  and  its  preparations  require  to  be  made 
with  particular  care  in  consequence. 

The  infusion,  extract,  and  confection,  in  all  of  which 
powdered  leaf  is  used,  are  prepared  according  to  the 
methods  officially  described  in  the  pharmacopoeias. 

An  examination  of  the  constituents  of  the  leaves  has 
been  made  by  Tutin  (T.  Chem.  Soc.  (1913),  103,  2006). 

COLOCYNTHIN,  the  principle  of  Colocynth.— Colocynth 
is  the  dried  pulp  of  the  fruit  of  Citrullus  Colocynthis,  Schrader, 
freed  from  its  seeds.  It  is  imported  from  Asia  Minor. 
Smyrna,  Spam,  Mogador,  Egypt  and  Cyprus,  also  from 
Persia. 

In  commerce  the  Turkish  and  Spanish  varieties  are  most 
frequently  met  with,  both  of  which  have  been  peeled  after 
drying.  The  Mogador  fruit  is  larger  and  unpeeled  ;  the 
Persian  colocynth  is  peeled  before  drying  and  presents, 
consequently,  a  shrunken  appearance. 


PURGATIVES  205 

A  boiled  and  cooled  aqueous  decoction  of  the  pulp  should 
yield  no  blue  colouration  with  starch  solution.  Between 
9  and  12  per  cent,  of  ash  should  be  afforded  on  ignition. 

Colocynth  pulp  is  an  intensely  bitter  substance  and 
acts  as  a  very  powerful  cathartic.  It  is  dangerous  in  large 
doses  and  is  not  commonly  prescribed  alone  but  in  small 
doses  in  conjunction  with  other  purgative  principles. 

The  active  principle,  colocynthin,  a  glucoside  to  which 
the  formula  C56H84O23  has  been  ascribed,  when  treated  with 
acids  is  hydrolysed  to  a  sugar  and  colocynthein,  which  is  said 
to  be  even  more  irritant  than  colocynthin. 

Colocynthin  is  obtained  from  an  extract  of  the  pulp, 
prepared  with  weak  alcohol.  This  is  dried  and  extracted 
with  cold  water.  The  filtered  extract  is  treated  with  lead 
acetate  solution,  and  filtered  again  from  the  precipitate 
which  is  produced.  The  filtrate  is  freed  from  lead  by  means 
of  sulphuretted  hydrogen,  and,  after  removal  of  excess  of 
the  latter,  is  precipitated  with  tannic  acid.  The  precipitate 
is  washed  with  water  and  decomposed,  in  alcoholic  solution, 
with  lead  oxide  (precipitated).  The  filtered  solution  is 
freed  from  lead,  decolourised  with  animal  charcoal,  and 
evaporated  to  dry  ness  in  vacuo.  The  resulting  product  is 
washed  with  anhydrous  ether.  It  consists  of  a  yellow, 
amorphous,  bitter-tasting  mass,  easily  soluble  in  water  and 
alcohol ;  insoluble  in  ether. 

It  possesses  a  powerful  purgative  action,  and  has  been 
employed  for  hypodermic  administration. 

JALAP. — The  official  jalap  consists  of  the  dried  tubers 
of  Ipomcea  purga,  Hayne.  It  is  mostly  imported  from 
Vera  Cruz,  but  is  cultivated  also  in  India  and  Jamaica. 
The  active  principles  have  not  been  isolated  from  the  resinous 
extract. 

Evaluation  of  Jalap. — A  weighed  quantity  (10  gms.)  of 
jalap  is  digested  at  a  gentle  heat  for  24  hours  with  twice 
its  weight  of  alcohol  (90  %),  transferred  to  a  percolator  and 
percolated  with  alcohol  until  nothing  further  is  dissolved. 
The  alcoholic  solution  is  precipitated  by  addition  of  water, 
the  alcohol  distilled,  the  residue  transferred  whilst  still  hot 


206         ORGANIC  MEDICINAL  CHEMICALS 

to  a  dish,  cooled,  and  the  supernatant  liquor  removed.  The 
resin  is  washed  with  hot  water,  dried  and  weighed.  It  should 
weigh  not  less  than  0*9  nor  more  than  1*1  gram  (B.P.). 

Jalap  should  not  afford  more  than  6  %  of  ash  on 
ignition. 

Jalap,  employed  either  as  the  powdered  drug  or  in  the 
form  of  an  extract,  is  a  powerful  cathartic,  operating  at 
times  painfully,  and  is  a  common  constituent  of  pills.  It  is 
especially  serviceable  in  dropsy  and  cerebral  congestion. 

Extract  of  Jalap  is  made  according  to  the  directions  of 
the  Pharmacopoeias.  One  part  of  coarsely -powdered  jalap 
is  extracted  first  with  5  parts  of  90  %  alcohol,  then  with 
10  parts  of  distilled  water,  and  the  two  residues  are  combined 
into  one  extract.  One  hundred  pounds  of  jalap  yield  about 
50  Ibs.  of  extract. 

Jalap  Resin  is  extracted  from  jalap  by  exhausting 
the  powdered  rhizome  with  alcohol  (90  %),  pouring  the  hot 
extract  with  stirring  into  water,  separating  the  oily  resin 
and  purifying  by  washing  it  with  hot  water.  It  is  best  dried  in 
a  vacuum  cupboard,  but  may  be  dried  over  a  steam  bath. 
After  cooling  it  is  pulverisable.  Jalap  resin  or  Jalapin  is  a 
grey-brown  friable  substance,  possessing  a  slight  character- 
istic taste  and  an  irritating  smell.  It  is  easily  soluble  in 
alcohol,  dissolves  in  50  parts  of  petrol  ether  and  in  10  parts 
of  ether.  Further,  it  dissolves  completely  in  acetic  acid, 
baryta  and  caustic  potash.  The  active  principle  of  jalap 
has  not  been  isolated.  Power  and  Rogerson  (/.  Am.  Chem. 
Soc.  (1901),  32,  80)  found  the  resin  to  be  of  very  complex 
composition.  Extracts  were  prepared,  employing  con- 
secutively different  solvents,  and  physiologically  tested,  with 
the  following  results  : — 

(1)  The  petroleum  extract  had  no  effect. 

(2)  The  ether  extract  produced  prompt  but  not  severe 
purgation. 

(3)  The  chloroform  extract  caused  repeated  purgation 
lasting  48  hours. 

(4)  The  ethyl  acetate  action  was  similar  in  its  action  to 
the  chloroform  extract,  purgation  lasting  24  hours. 


PURGATIVES  207 

(5)  The  alcohol  extract  produced  repeated  and  violent 
purgation. 

From  this  it  is  presumed  that  the  purgative  action  is 
not  due  to  any  single  or  well-defined  constituent. 

SCAMMONY  RESIN. — Scammony  resin  is  obtained  by  ex- 
tracting with  hot  alcohol  the  root  of  Convolvulus  Scammonia. 
Most  of  the  solvent  is  removed  by  distillation,  after  which 
the  hot  concentrated  solution  is  poured  into  water,  which 
precipitates  the  resin.  The  resin  is  repeatedly  washed  with 
hot  water,  separated  and  dried  in  vacuo  or  in  an  open 
steam  pan.  Mexican  scammony  resin — the  gum-resin 
afforded  by  the  root  of  Ipomcea  orizabensis — closely  resembles 
genuine  scammony  resin  in  its  chemical  and  physical 
properties  and  physiological  action,  but  is  not  identical. 
Both  these  resins  have  a  similar  action  to  that  of  jalap 
resin,  being  energetic  hydragogue  cathartics.  They  are 
valuable  when  brisk  action  is  needed,  as  in  severe  dropsy 
and  in  cerebral  congestion.  They  also  act  as  anthelmintics 
to  round  worms  and  tape  worms. 

Scammony  resin  is  met  with  in  greenish-grey,  or  brownish- 
green,  translucent  brittle  lumps,  with  more  or  less  sharp 
edges,  and  breaking  with  a  shining  fracture.  It  is,  in  contra- 
distinction to  jalap  resin,  almost  completely  soluble  in  ether. 
The  acid  value  should  be  14*6,  the  ester  value  171*0,  and  the 
saponification  value  185*6.  It  should  yield  not  more  than 
ro  %  of  ash. 

Virgin  Scammony  is  a  gum  resin  obtained  by  incision 
of  the  living  root  of  Convolvulus  Scammonia.  It  is  derived 
chiefly  from  Asia  Minor  and  constitutes  brown,  dark-grey, 
or  brownish-black,  irregular  masses,  or  circular  cakes, 
which  break  with  a  glossy  resinous  fracture.  It  forms 
with  water  a  greenish  emulsion  (distinction  from  scammony 
resin).  When  treated  with  ether,  at  least  70  %  should  be 
dissolved. 

Aleppo  scammony  has  an  acid  value  of  8*2,  an  ester 
value  of  172,  and  a  saponification  value  of  180*2.  Not  more 
than  3-0  %  of  ash  should  be  left  on  ignition. 

Power  and  Rogerson  (T.  Chem.  Soc.  (1912),  roi,  398) 


208         ORGANIC  MEDICINAL   CHEMICALS 

have  found  these  resins  of  scammony  to  be  exceedingly 
complex  in  character.  Though  similar  in  their  general 
characteristics  they  are  not  perfectly  identical.  They 
appear  to  consist  to  a  large  extent  of  the  glucosides  and 
rhamnosides  of  jalapinolic  acid  Ci5H30(OH)COOH  and  its 
methyl  ester.  The  resin  from  Mexican  scammony  root, 
Ipomcea  orizabensis,  on  the  other  hand,  differs  from  them  very 
considerably.  Amongst  other  differences  may  be  mentioned 
the  fact  that  it  affords  on  hydrolysis  a  methylpentoside 
differing  from  rhamnose. 

Podophyllin. — Podophyllin  is  the  resin  obtained  from 
the  dried  rhizome  and  roots  of  Podophyllum  peltatum,  a 
plant  which  grows  wild  in  North  America.  It  is  an  active 
cholagogue,  and,  in  J  gr.  doses,  acts  as  a  powerful  purgative. 

Although  the  American  species  only  is  official  in  the 
British  Pharmacopoeia,  Dunstan  and  Henry  (T.  Chem.  Soc. 
(1898),  73,  209)  have  shown  that  the  constituents  of  the 
Indian  species,  P.  emodi,  are  identical  with,  though  in  different 
proportion  to,  those  of  P.  peltatum  ;  furthermore,  P.  emodi 
contains  a  higher  percentage  of  resin.  The  chief  active 
principles  in  these  two  varieties  are  podophyllo-toxin 
Ci5H14O6'2H2O  and  a  podophyllo-resin.  The  former,  how- 
ever, is  unsuitable  as  a  medicinal  substitute  for  podophyllin 
resin  on  account  of  its  intensely  irritating  action,  whilst  the 
use  of  the  resin  constituent  seemed  to  present  no  advantage 
over  the  drug  as  generally  employed  ;  other  constituents  are 
podophyllo-quercitin  and  picropodophyllin.  The  latter  is 
isomeric  with  podophyllo- toxin  and  has  been  given  the  follow- 
ing probable  formula  by  Dunstan  and  Henry  (T.  Chem.  Soc. 
(1898),  73,  209)  :- 

, C02 


°KS 


.— CH/° 


\/ 

CHg 

Picropodophyllin. 


PURGATIVES  209 

Podophyllin  resin  is  prepared  by  extracting  the  powdered 
root  with  hot  alcohol,  concentrating  the  extract,  and  pouring 
it  into  cold  acidified  water  with  vigorous  stirring  ;  the 
temperature  should  be  kept  low  and  ice  employed,  if  neces- 
sary, to  prevent  coagulation  of  the  precipitate.  The 
precipitated  resin  is  filtered  off,  washed  and  dried  at  a  low 
temperature. 

Podophyllin  resin  is  a  light  yellow  powder.  It  is  sparingly 
soluble  in  water,  almost  completely  soluble  in  alcohol  (90  %) 
and  in  ammonia  solution.  The  quantity  insoluble  in  alcohol 
should  not  exceed  five  per  cent. 

More  than  50  %  of  the  resin  should  be  soluble  in  cold 
chloroform.  Not  moie  than  i  %  of  ash  should  be  left  on 
ignition. 

The  resins  from  P.  emodi  and  P.  peltatum  may  be  dis- 
tinguished by  the  following  test.  Six  grains  of  the  resin 
are  mixed  with  i  fluid  dram  of  dilute  alcohol  and  8  to  10 
drops  of  caustic  potash  solution  (6*2  %  KOH).  The  resin 
of  P.  peltatum  affords  a  deep  yellow  solution  on  shaking,  that 
of  P.  emodi  a  semi-solid  gelatinous  mass. 

C(C6H4OH)2 


PHENOL-PHTHALEIN  (purgen)  !    j      >O  318.— 

CO 

Baeyer's  original  method  (Ann.  (1880),  202,  69)  still  remains 
the  only  one  published  which  deals  with  the  preparation  of 
phenol-phthalein. 

Cs-(C6H4OH)2 

+H2O 


A  solution  of  250  grams  of  phthalic  anhydride  in  200 
grams  of  concentrated  sulphuric  acid  is  prepared  with 
careful  heating.  It  is  cooled  to  115°,  and  treated  with 
500  grams  of  phenol,  and  the  mixture  is  then  heated  at 
H5°-I20°  for  10-12  hours,  care  being  taken  that  the  temper- 
ature does  not  exceed  120°.  The  melt  is  tlfen  poured  into 
boiling  water,  and  the  excess  of  phenol  removed  by  steam 

i.  14 


210          ORGANIC  MEDICINAL  CHEMICALS 

distillation.  The  granular  yellow  solid  is  extracted  with 
dilute  caustic  soda,  which  dissolves  out  the  phenol-phthalein, 
leaving  behind  a  by-product,  phthalein  anhydride.  After 
cooling,  the  liquid  is  filtered,  acidified  with  acetic  acid, 
mixed  with  a  few  drops  of  hydrochloric  acid,  and  left  to 
stand  for  24  hours.  The  crude  phenol-phthalein,  a  sandy- 
yellow  powder,  is  then  filtered  off  and  dried.  To  purify  it 
for  pharmaceutical  use  it  must  be  crystallised.  Ten  parts 
of  the  air-dried  crude  product  are  boiled  under  reflux  for 
i-|  hours  with  60  parts  of  absolute  alcohol  and  5  parts  of 
dry  animal  charcoal.  The  mass  is  filtered  while  still  hot, 
the  charcoal  being  washed  with  20  parts  of  boiling  alcohol. 
The  combined  filtrates  are  concentrated  to  two-thirds  their 
original  volume,  and  treated  with  water  ;  the  milky  liquid 
deposits,  on  standing,  crystals  of  phenol-phthalein  mixed 
with  a  gummy  impurity.  To  remove  this,  the  alcoholic 
solution  is  added  to  water,  in  the  proportion  of  40  grams  to 
320  c.c.,  the  mixture  is  vigorously  shaken,  and  after  standing 
for  a  short  time  separated  quickly  from  the  precipitated 
resin.  The  solution  is  then  heated,  when  the  milkiness 
disappears,  a  white  crystalline  powder  being  precipitated. 
This  is  filtered  off,  washed  with  water,  and  dried  at  a  low 
temperature.  A  further  quantity  is  obtained  by  removal 
by  distillation  of  the  alcohol  from  the  filtrate.  The  yield 
is  given  as  75  %,  calculated  from  the  weight  of  phthalic 
anhydride  employed. 

Phenol-phthalein  forms  a  white  powder,  almost  insoluble 
in  water  ;  readily  soluble  in  alcohol.  M.p.  25o°-253°.  It  dis- 
solves completely  in  sodium  or  potassium  hydroxide  solution. 

Phenol-phthalein  is  employed  in  medicine  as  an  aperient, 
and  is  the  only  synthetic  purgative  which  has  found 
wide  acceptance.  Its  action  is  maintained  mildly  for 
several  days.  This  is  explained  by  the  fact  that  it  is  ab- 
sorbed in  the  blood  and  excreted  by  the  bile  duct  into  the 
gut  again. 

Tetrachlorpphenol-phthalein  exerts  a  similar  action  to 
that  of  phenol-phthalein  itself. 


SECTION  VII.—  VASO-CONSTRICTORS  AND 
VASODILATORS 

THE  usual  products  of  tissue  metabolism  exercise  a  dilator 
action  on  the  blood  vessels  ;  this  action  is  balanced  partly  by 
sympathetic  nerve  reflexes,  but  also  by  a  substance  secreted 
by  the  supra-renal  gland  (adrenaline)  which  exerts  a  very 
powerful  constrictor  action.  This  has  been  termed  by 
Barger  and  Dale  sympathomimetic  action.  The  elucidation 
of  the  chemical  constitution  of  adrenaline  pointed  the  way  to 
the  preparation  of  other  substances  of  analogous  constitution 
which  possess  like  action.  Adrenaline  has  the  constitution  : 


CH2—  NH—  CH3 
OH 

If  the  hydroxyl  group  of  the  side  chain  is  substituted  by 
hydrogen,  the  compound  (epinine)  has  a  like  though  weaker 
action,  and  is  also  used  in  medicine. 

During  an  investigation  of  the  substances  responsible 
for  the  well-known  pressor  action  of  ergot,  what  may  be 
regarded  as  a  parent  substance  of  adrenaline,  para-hydroxy- 
phenyl-ethylamine  (tyramine)  OH<^^—  CH2CH2NH2, 

OH 

proved  to  have  similar  physiological  properties.  Following 
this  discovery  many  other  amines  were  found  to  act  in  this 
way.  Of  most  especial  value  and  importance  is  jS-iminazolyl- 
ethylamine  (histamine),  also  present  in  ergot. 

Ergot  has  long  been  employed  hi  medicine  for  its  pressor 
action  and,  strangely,  it  yields,  in  addition  to  the  two 
substances  referred  to  above,  an  alkaloid  of  complex  consti- 
tution (as  yet  unknown)  which  also  acts  powerfully  as  a 


212         ORGANIC  MEDICINAL  CHEMICALS 

vaso-constrictor  ;  this,  as  well  as  the  bases,  tyramine,  hista- 
mine  and  adrenaline,  are  dealt  with  more  fully  in  the  follow- 
ing pages. 

The  nitrites  exert  an  opposite  (vaso-dilator)  action  on  the 
arteries ;  they  also  are  here  described.  Organic  nitric 
esters  act  similarly  to  nitrites  on  the  blood  vessels  through 
becoming  reduced  to  nitrites  in  the  tissues  ;  thus  nitro- 
glycerin  acts  similarly  to,  but  more  slowly  than,  amyl  nitrite. 
ERGOTOXINE  C35H41O6N6.  627.— -Ergotoxine  is  the 
physiologically  active  alkaloid  of  ergot — the  mycelium  of  a 
fungus,  Claviceps  purpurea,  which  is  developed  on,  and 
takes  the  place  of,  the  growing  ovary  of  the  rye  plant,  Secale 
cornutum. 

The  principal  commercial  varieties  of  ergot  are  derived 
from  Russia,  Spain,  Germany  and  Austria.  Ergot  should 
be  hard  and  dry,  flexible  and  damp  specimens  being  inferior. 
It  should  be  kept  dry,  and  not  longer  than  a  year  owing  to 
its  liability  to  be  destroyed  by  weevils. 

For  the  preparation  of  ergotoxine  powdered  ergot  is 
completely  extracted  with  ether  and  the  ether  extract  is 
concentrated  to  an  oily  residue,  which  is  extracted  with 
aqueous  0*5  per  cent,  tartaric  acid  solution.  The  filtered 
acid  extract  is  shaken  out  with  ether  and  rendered  alkaline 
with  sodium  carbonate,  and  the  precipitated  alkaloid 
(amounting  to  o '2  to  0-25  %  of  the  drug)  is  extracted  with 
ether.  The  ether  extract  is  washed  and  dried  at  a  low 
temperature.  It  is  dissolved  in  methyl  alcohol,  wherefrom 
ergotinine  crystallines.  The  filtrate  from  this,  which  con- 
tains the  ergotoxine,  is  dissolved  in  3  parts  of  acetic  acid,  the 
solution  is  diluted-  to  300  parts,  filtered,  and  treated  with 
100  parts  of  an  aqueous  solution  containing  I  part  of  anhy- 
drous NaSO4.  The  sparingly  soluble  ergotoxine  sulphate 
crystallises  out,  whilst  ergotinine  remains  in  solution.  The 
sulphate  is  purified  by  recrystallisation.  Another  suitable 
salt  for  the  purification  process  is  the  phosphate,  which  may 
be  crystallised  from  80  per  cent,  alcohol. 

An  alternative  method  of  preparation  is  as  follows  : — 
An  alcoholic  extract  of  ergot  is  prepared  and  the  solvent 


VASO-CONSTRICTORS  AND   VASO-DILATORS    213 

removed  by  distillation.  The  residue  is  extracted  with 
light  petroleum  to  remove  fat,  etc.,  dissolved  in  ethyl 
acetate  and  shaken  with  citric  acid  solution.  Sodium 
bromide  is  added,  when  the  sparingly  soluble  hydrobromides 
are  precipitated  and  are  filtered  off. 

The  mixed  hydrobromides  are  dissolved  in  dilute  caustic 
soda,  and  the  solution  extracted  with  ether,  which  dissolves 
out  the  ergotinine,  mixed  with  a  little  ergotoxine.  The 
ether  is  removed  and  the  ergotinine  crystallised  from  absolute 
alcohol,  from  which  it  separates  in  long  needles. 

Ergotinine  can  be  converted  into  ergotoxine  by  boiling 
it  with  dilute  acetic  or  phosphoric  acid  in  dilute  alcohol. 
The  liquor  from  which  the  ergotinine  has  been  extracted  is 
neutralised,  made  alkaline  with  sodium  carbonate,  and 
shaken  out  with  ether.  The  residue  left  after  evaporation 
of  the  ether,  together  with  that  from  the  ergotinine  mother 
liquors,  is  dissolved  in  80  %  alcohol  and  treated  with  a  slight 
excess  of  phosphoric  acid  dissolved  in  alcohol.  Ergotoxine 
phosphate  separates  out  on  standing  and  is  filtered  off  and 
recrystallised  from  90  %  alcohol. 

Ergotoxine  Phosphate  C35H41O6N5-H3P(VH2O  is  the 
most  readily  prepared  salt  of  ergotoxine.  It  forms  an 
almost  white  crystalline  powder.  M.p.  i86°-i87°.  It 
dissolves  in  14  parts  of  boiling,  or  313  parts  of  cold,  90  % 
alcohol ;  with  cold  water  it  gives  a  colloidal  solution. 

Ergotoxine  hydrochloride,  sulphate  and  oxalate  are 
crystallisable. 

Ergotoxine  Alkaloid  is  a  white  amorphous  powder. 
M.p.  i6o°-i62°.  It  is  almost  insoluble  in  water  ;  easily 
soluble  in  alcohol,  ether  and  in  boiling  benzene.  It  is  a 
carboxylic  acid  derivative  and  forms  the  lactone,  ergotinine. 

Ergotoxine  exerts  a  powerful  action  upon  the  tissues  and 
causes  rhythmic  contraction  of  the  uterus.  It  does  not 
possess  all  the  characteristic  actions  of  ergot  extracts,  which 
owe  their  activity  also  to  the  presence  of  ^-hydroxyphenyl- 
ethylamine  (tyramine)  and  /3-iminazolyl-ethylamine  (hista- 
mine).  Barger  and  Carr  (Trans.  (1907),  337),  Kraft  (Arch, 
der  Pharm.  (1906),  244,  336). 


214         ORGANIC  MEDICINAL  CHEMICALS 


ERGOTININE  CssH^gC^N^  609,  is  the  lactone  of  ergotoxine, 
from  which  it  may  be  derived  by  treatment  with  boiling 
methyl  alcohol  or  by  the  action  of  acetic  anhydride.  It  is 
crystallised  from  absolute  alcohol,  from  which  it  separates 
in  long  needles,  or  from  ether.  M.p.  2i9°-22O°.  It  is  readily 
soluble  in  acetone,  ethyl-acetate  and  benzene,  less  so  in 
alcohol  (i  in  290  parts)  and  in  ether  (i  in  1000  parts).  It 
does  not  form  crystalline  salts. 

A  solution  in  methyl-  or  ethyl-alcohol  slowly  undergoes 
decomposition.  A  solution  in  acetic  or  phosphoric  acid 
undergoes  gradual  conversion  into  the  salt  of  ergotoxine. 

Ergotinine  does  not  exert  any  notable  physiological 
action. 

Other    active    substances    from    ergot    are    ^-hydroxy- 

phenyl-ethylamine  OH^~^>CH2CH2NH2,  which  has  been 
synthesised  and  introduced  into  medicine  under  the  name 
of  tyramine,  and  j3-iminazolyl-ethylamine  or  4-j8-amino- 
ethyl-glyoxaline  (histamine) 

—  CH 


-     C'CH2—  CH2—  NH2 

These  bases  were  isolated  from  ergot  extract  by  Barger 
and  Dale  (Trans.  Chem.  Soc.  (1909),  95,  1125  and  (1910),  97, 
2592),  also  by  Kutscher  (Zeits.  Physiol.  (1910),  24,  163). 

Of  the  bases  enumerated  above,  ergotoxine  causes  con- 
traction of  the  uterus,  rise  of  blood  pressure,  and  gangrene 
of  the  cock's  comb  ;  ^-hydroxy-phenyl-ethylamine  causes 
uterine  contraction  and  rise  of  blood  pressure  ;  j3-iminazolyl- 
ethylamine  produces  a  very  rapid  rise  of  blood  pressure, 
also  contraction  of  the  uterus,  Ergotinine  has,  when  un- 
changed in  the  system,  only  a  very  slight  action,  but 
is  liable  to  be  converted  into  the  physiologically  active 
ergotoxine. 

TYRAMINE  (^-hydroxy-phenyl-ethylamine) 


137- 
— Tyramine  was  isolated  from  ergot  extract  by  Barger  and 


VASO-CONSTRICTORS  AND   VASO-DILATORS    215 

Dale,  and  is  present  in  putrefactive  animal  matter.    It  may 
be  derived  from  tyrosine  by  loss  of  CO2  '.  — 


/--  \ 
OH<    >CH2CH 

NH2 

Several  methods  of  preparing  it  synthetically  have  been 
put  forward. 

(i)  Benzyl  cyanide  is  reduced  to  phenyl-ethylamine, 
and  this  compound  is  benzoylated,  nitrated,  reduced,  diazo- 
tised  and  hydrolysed  :  — 


;H2CN  CH2CH2NH2  CH2CH2NH-COCGH5 

N02  NH2  OH 


CH2CH2NHCOC6H5  CH2CH2NHCOC,H6  CH2CH2NH2 

(2)  Anisic    aldehyde   is   condensed   with   ethyl-acetate, 
using-  sodium,  and  the  product  is  subsequently  boiled  with 
alcoholic  potash.     The  methoxy-phenyl-propionic  acid  thus 
produced  is  converted  into  its  chloride,  by  the  action  of 
phosphorus  pentachloride,  and  thence  into  its  amide,  with 
gaseous  ammonia.    Thence  to  ^-methoxy-phenyl-ethylamine, 
from  which   the  methoxy  group  is  split  off  by  treatment 
with  hydrobromic  or  hydriodic  acid  under  pressure. 

(3)  Anisic  aldehyde  is  condensed  with  nitro-methane  to 
form  j3-nitro-_£-methoxy-styrene,  which   is   reduced   to  p- 
methoxy-phenyl-ethylamine  and  the  methoxy  group  split 
off  as  under  method  (2). 

HISTAMINE    (/Mminazolyl-ethylamine,    4-j8-amino-ethyl- 

,NH— CH 
glyoxaline)  CH^  ||  in. — Histamine 

^N C-CH2-CH2'NH2 

was  first  isolated  by  Barger  and  Dale  from  ergot  extract. 
It  may  be  obtained  from  histidine — 

NH— CH         COOH 

II  I 

N C'CH2— CH-NH2 


2i6         ORGANIC  MEDICINAL  CHEMICALS 

an  amino  acid  which  occurs  as  a  product  of  hydrolysis  of  many 
albumens,  notably,  in  considerable  amount,  of  haemoglobin. 

Histidine  itself  has  been  synthesised  by  Pyman  (Trans. 
Chem.  Soc.  99,  1086  (1911)  ;  109,  186  (1916)).  The  same 
investigator  has  also  effected  a  direct  synthesis  of  histamine, 
starting  with  diamino-acetone  hydrochloride  (Trans.  Chem. 
Soc.  99, 668  (1911)),  and  has  succeeded,  in  collaboration  with 
Bwins,  in  obtaining  a  25  %  yield  of  histamine  from  histidine 
by  heating  the  latter  with  hydrochloric  acid  (Trans.  Chem. 
Soc.  99,  339  (1911)).  The  synthetic  methods  of  preparing 
histidine,  however,  involve  many  steps,  and  it  is  possible 
that  it  is  best  prepared  technically  by  the  hydrolysis  of 
haemoglobin. 

It  is  claimed,  in  D.  R.  P.  252873,  that  good  yields  of  pure 
histamine  can  be  obtained  from  the  products  of  the  hydro- 
lysis of  blood.  One  kilo  of  blood  is  hydrolysed  by  boiling 
with  4  kgs.  of  25  %  sulphuric  acid  for  16-20  hours.  Excess 
of  the  acid  is  removed  by  treatment  with  baryta,  and  the 
solution  concentrated  to  700  c.c.  The  amino  acids  which 
separate  on  cooling  contain  no  histidine  and  are  filtered  off. 
The  filtrate  is  mixed  with  500  c.c.  of  alcohol  and  evaporated 
to  dryness,  and  the  residue  then  macerated  with  i  litre  of 
alcohol,  when  about  80  grams  of  amino  acids,  histidine  free, 
pass  into  solution  and  are  removed  by  filtration.  The 
residual  mass  is  dried  in  vacuo.  It  weighs  about  420  grams, 
and  contains  (estimated  from  the  yield  of  histamine  it 
affords)  about  120  to  140  grams  of  histidine. 

This  is  treated  according  to  D.  R.  P.  252872,  in  which  a 
solution  of  10  grams  of  histidine  hydrochloride  in  800  c.c. 
of  water  is  fermented  at  37°-39°,  with  5  c.c.  of  an  autolysate 
from  15  grams  of  thymus  gland  in  100  c.c.  of  water,  or  with 
a  pure  culture  obtained  therefrom  (D.  R.  P.  256116).  The 
fermentation  is  allowed  to  continue  until  the  quantity  of 
histamine  present,  estimated  by  conversion  into  its  picrate, 
no  longer  increases,  and  is  usually  completed  in  5  to  6  days, 
when  i  part  of  the  above  solution  should  give  O'OiS  to 
0-019  part  of  histamine  picrate,  an  amount  almost  corre- 
sponding to  a  theoretical  yield. 


VASO-CONSTRICTORS  AND   VASO-DILATORS    217 

The  solution  of  histamine  may  then  be  treated  with 
picric  acid,  the  picrate  filtered  off,  recrystallised  (m.p.  228°), 
and  converted  into  the  hydrochloride  by  treating  with  the 
required  quantity  of  hydrochloric  acid,  shaking  out  the 
picric  acid  with  a  solvent,  such  as  ether,  and  then  evaporating 
to  dryness.  A  kilogram  of  blood  should  afford  107  grams 
of  histamine  hydrochloride. 

Alternatively,  D.  R.  P.  252874,  the  solution  after  fer- 
mentation is  acidified  with  hydrochloric  acid  and  evaporated 
to  a  syrup,  which  is  made  alkaline,  and  mixed  with  sufficient 
anhydrous  sodium  sulphate  to  give  a  pulverisable  mass 
after  powdering.  This  is  extracted  with  hot  chloroform, 
from  which,  after  concentration  and  on  cooling,  the  histamine 
separates  in  crusts. 

A  method  of  fermentation  is  described  in  D.  R.  P.  250110, 
whereby  decomposing  pancreas  is  employed.  The  process  is 
stated  to  occupy  seven  weeks.  The  histamine  is  purified  by 
conversion  into  its  mercury  salt,  from  which  it  is  regenerated 
by  H2S.  One  hundred  parts  of  histidine  hydrochloride  are 
said  to  yield  60  parts  of  histamine  hydrochloride. 

ADRENALINE  (epinephrine,  adrenine,  suprarenine) 

OH 

)H  183. 


QO, 


CHOH-CH2'NHCH3 

Adrenaline  is  the  active  principle  of  the  suprarenal  gland, 
from  which  it  was  first  isolated  in  a  pure  state  by  Takamine 
(Amer.  Journ.  Pharm.  (1901),  73,  523),  though  Abel  had 
previously  obtained  it  in  impure  form.  The  naturally  occur- 
ring base  is  the  laevo-stereoisomeride,  which  has  about  twice 
the  activity — judged  by  the  augmentation  of  the  blood 
pressure — of  the  synthetically  obtained  racemic  substance. 
The  synthetic  laevo-base  obtained  from  the  latter  is 
identical  in  all  respects  with  the  natural  active  principle. 

Preparation  of  the  Glands. — Minced  fresh  suprarenal 
glands  of  the  ox  or  sheep,  containing  about  0*2  per  cent. 
of  adrenaline,  are  exhausted  by  successive  extractions  with 


2i8         ORGANIC  MEDICINAL  CHEMICALS 

boiling  acidified  water,  a  little  zinc  dust  being  added. 
The  filtered  extract  is  evaporated  down  in  vacuo  at  50° 
to  a  syrupy  condition  ;  it  is  then  mixed  with  several  volumes 
of  ethyl  or  methyl  alcohol  and  may  be  treated  with  lead 
acetate  solution  until  this  reagent  produces  no  further  pre- 
cipitation. The  filtrate  from  this  (after  being  freed  from 
lead  by  H2S  if  lead  acetate  has  been  added)  is  evaporated 
in  a  current  of  CO2,  or  in  vacuo,  to  a  syrupy  consistence,  a 
layer  of  paraffin  is  added  and  then  an  excess  of  concentrated 
ammonia  solution.  A  crystalline  precipitate  of  adrenaline 
gradually  forms  ;  it  is  filtered  off,  washed  successively  with 
water,  alcohol  and  ether,  and  dried  in  a  vacuum  over 
concentrated  sulphuric  acid.  It  can  be  purified  further 
by  solution  in  dilute  hydrochloric  acid  and  reprecipita- 
tion  with  ammonia.  To  prevent  oxidation  it  is  useful  to 
keep  sulphites  present  during  the  above  operations.  The 
crude  base  may  be  purified  by  being  ground  up  with  a 
strong  solution  of  oxalic  acid  in  90  per  cent,  alcohol,  which 
leaves  inorganic  impurities  behind  ;  these  are  filtered  off 
and  the  adrenaline  is  precipitated  with  ammonia. 

A  large  number  of  processes  for  preparing  adrenaline 
synthetically  have  been  devised  ;  of  them  the  following  is 
of  chief  technical  value.  The  starting  out  materials  are 
pyrocatechol  and  chloracetyl  chloride  (or  chloracetic  acid 
and  phosphorus  oxychloride)  and  the  synthesis  is  effected 
according  to  the  following  scheme  :  — 

OH  OH 

)H+CH2C1COC1    -> 


CO—  CH2C1 

Pyrocatechol.  Chloraceto-catechol. 

OH  OH 


COCH2NHCH3  CHOH—  CH2NHCH  3 

Amino-methyl-acetocatechol  (adrenalone).  r-adrenaline. 

Chloraceto-catechol   (D.  R.  P.  71312).  —  Pyrocatechol,  10 
parts,   is  mixed    with    chloracetyl    chloride,   8  parts,   and 


VASO-CONSTRICTORS  AND   VASO-DILATORS    219 

the  mixture  carefully  heated  until  evolution  of  HC1  has 
commenced,  when  the  reaction  completes  itself.  The 
chloraceto-catechol  which  is  thus  produced  is  recrystallised 
from  water,  employing  charcoal  as  a  decolourising  agent, 
and  is  obtained  in  the  form  of  colourless  needles.  M.p. 

173°. 

Bromaceto-catechol  may  be  prepared  similarly,  by 
employing  bromacetyl  Bromide  or  bromacetyl  chloride. 
M.p.  170°. 

OH 


Methylamino-acetocatechol  \    y  (D. 


R.    P. 


COCH2NHCH3 
152814). — Finely  powdered  chloraceto-catechol,  i  part,  is 
suspended  in  i  volume  of  alcohol,  and  i  part  of  aqueous 
60  %  methylamine  solution  added.  Heat  is  developed  and 
the  methylamine  salt  of  the  chlor-dioxy  ketone  is  formed. 
This  is  gradually  converted,  on  maintaining  the  solution  at 
a  moderate  temperature,  into  methylamino-acetocatechol, 
which  separates  as  a  crystalline  precipitate.  This,  after 
standing  for  i  hour,  is  filtered  off  and  washed  with  cold 
alcohol.  It  is  purified  by  dissolving  it  in  dilute  hydro- 
chloric acid  and  carefully  treating  the  solution  with  ammonia, 
when  a  small  quantity  of  amorphous  impurity  separates 
and  is  filtered  off  before  the  bulk  of  the  base  is  precipitated. 

Methylamino-acetocatechol  forms  clear  yellow  crystals, 
which  on  heating  colour  at  200°  and  decompose  at  230°. 

The  hydrochloride  crystallises  from  alcohol  in  colourless 
leaflets,  which  decompose  on  heating  at  240°. 

Reduction  of  Methylamino-acetocatechol  to  Adrenaline 
(T>.  R.  P.  157300). — One  part  of  methylamino-acetocatechol  is 
dissolved  in  30  parts  of  hot  water  containing  the  calculated 
quantity  (|  mol.)  of  sulphuric  acid.  The  solution  is  heated 
on  a  water  bath  and  to  it  are  added  i  part  of  a  i  % 
solution  of  mercuric  sulphate  and  i  part  of  aluminium  foil 
The  mixture  is  heated  and  stirred  for  3-4  hours,  during  which 
time  the  base  which  separates  is  brought  into  solution  by 
successive  and  careful  additions  of  sulphuric  acid.  When  the 


220         ORGANIC  MEDICINAL  CHEMICALS 

reduction  is  finished,  any  excess  of  acid,  and  the  alumina, 
are  precipitated  by  exact  neutralisation  with  baryta,  filtered 
off,  and  the  solution  evaporated  to  dry  ness  in  vacuo.  The 
sulphate  of  the  methylamino-ethanol-catechol  is  obtained 
as  an  amorphous  mass.  This  is  dissolved  in  water,  and  made 
alkaline  with  ammonia,  when  the  adrenaline  is  precipitated 
as  a  crystalline  powder,  whicrHs  filtered  oft. 

r-Adrenaline  Hydrochloride  is  prepared  (D.  R.  P. 
202169)  by  moistening  the  base  with  absolute  alcohol  and 
dissolving  in  absolute  alcohol  containing  the  theoretically 
necessary  quantity  of  hydrogen  chloride.  The  hydrochloride 
crystallises  out  on  standing  and  is  filtered  off,  washed  with 
ether,  and  recrystallised  from  absolute  alcohol. 

Colourless  crystals.  M.p.  157°.  Readily  soluble  in 
water. 

Resolution  of  r-Adrenaline  into  Isevo-  and  dextro- 
Adrenaline. — According  to  D.  R.  P.  222451  fifty  grams  of 
racemic  adrenaline  are  moistened  with  absolute  methyl  or 
ethyl  alcohol  and  treated  with  an  alcoholic  solution  of  43 
grams  of  dextro-tartaric  acid.  The  alcohol  is  removed 
in  vacuo  at  35°-40°  and  the  tartrate  dried.  The  salt  is 
ground  up  with  methyl  alcohol,  whereupon  the  tartrate  of 
dextro-adrenaline  dissolves.  The  laevo-adrenaline  ^-tartrate 
is  then  purified  by  being  recrystallised  from  95  %  methyl 
alcohol,  until  it  has  a  melting  point  of  149°.  The  liquors 
from  the  above  preparation,  which  contain  the  dextro- 
adrenaline,  are  'freed  from  alcohol,  the  residue  is  dissolved  in 
water  and  the  ^-adrenaline  recovered  by  precipitation  with 
ammonia.  It  may  then  be  racemised  (D.  R.  P.  220355)  by 
dissolving  15  parts  in  135  c.c.  of  normal  hydrochloric  acid 
and  150  c.c.  of  water,  and  heating  the  solution  at  8o°-9O° 
until  it  has  become  optically  inactive  (2-3  hours).  The 
base  is  then  precipitated  with  ammonia  and  reconverted 
into  the  ^-tartrate.  'Organic  acids,  such  as  tartaric  and 
oxalic  acids,  can  also  be  employed  for  the  racemisation  of 
^-adrenaline  (D.  R.  P.  223839). 

A  modification  of  the  above  method  of  resolving  racemic 
adrenaline  is  given  in  D.  R.  P.  269327.  r- adrenaline,  182 


VASOCONSTRICTORS  AND   VASO-DILATORS    221 

parts,  is  dissolved,  together  with  150  parts  of  dextro-tartaric 
acid,  in  1000  parts  of  hot  methyl  alcohol.  L,sevo-adrenaline 
d-tartrate  crystallises  out  on  cooling,  and,  after  several  days' 
standing,  is  filtered  off  and  purified  by  being  twice  recrystal- 
lised  from  methyl  alcohol. 

Other  methods  of  preparing  r-adrenaline  are  :  — 
(i)  Diacetyl-proto-catechuic  aldehyde  (I)  on  condensa- 
tion with  nitro-methane  in  feebly  alkaline  aqueous  solution 
yields  j8-hydroxyrj8-3  :  4-diacetoxy-phenyl-nitro-ethane  (II). 
When  this  is  mixed  with  the  calculated  quantity  of  formalde- 
hyde and  reduced  by  zinc  and  acetic  acid,  j8-hydroxy-j3- 
3  :  4-diacetoxy-phenyl-ethyl-methylamine  (III)  is  formed, 
from  which  adrenaline  is  obtained  on  removal  of  the  acetyl 
groups. 

OAc  OAc  OAc 

AOAC  ^   AOAC  ^ 

\y  \/. 

CHO  CH(OH)-CH2-NOo  CH(OH)'CH2'NHMe 

(I)  (II)   '  (III) 


(N.  Nagai,  Jap.  Pats.  32440,  32441 

(2)  From  proto-catechuic  aldehyde  cyanhydrin  (D.  R.  P. 

220355)    by   reduction    to    OH<^>CHOH'CH2NH2   and 

OH 
methylation  of  this. 

(3)  From  the   methylene-dioxyphenyl-ethylene-halogen- 
hydrins,  by  treatment  with  PC15,  then  with  water  and  methyl- 
amine  (D.  R.  PP.  209962,  216640,  209609). 

(4)  By  D.  R.  PP.  185598  and  189483,  a  catechol  ether, 
such  as  veratrol,  is  combined  with  phthalyl-glycyl  chloride, 
giving  the  corresponding  ether  of  phthalimido-acetocatechol. 
This,  on  treatment  with  hydrochloric  acid  in  glacial  acetic 
acid  solution,  is  hydrolysed  into  phthalic  acid  and  amino- 
ace  to-  catechol,  which  can  be  made  to  yield  adrenaline  by 
methylation  and  reduction. 

Racemic  adrenaline  is  a  white  crystalline  powder,  which 
decomposes  at  230°  C.  L,aevo-adrenaline  forms  small  white 
acicular  crystals. 


222         ORGANIC  MEDICINAL  CHEMICALS 

M.p.  212°  with  decomposition.  MD— 53°  (in  dilute 
hydrochloric  acid).  Sparingly  soluble  in  cold  water,  in- 
soluble in  alcohol  and  in  ether.  Soluble  in  dilute  acids  and 
caustic  alkali. 

The  aqueous  solution,  particularly  when  alkaline,  rapidly 
absorbs  oxygen  from  the  air,  becoming  pink,  red  and 
eventually  brown,  this  constituting  a  delicate  reaction  for 
the  identification  of  adrenaline  in  small  amounts. 

The  chief  crystalline  salt  is  the  acid  tartrate.  The 
racemic  base  forms  a  crystalline  hydrochloride  and  oxalate, 
but  the  corresponding  salts  of  the  laevo  modification  are 
amorphous. 

Adrenaline  acts  by  constricting  the  blood  vessels,  causing 
a  large  rise  of  blood  pressure.  It  also  stimulates  the  vagus 
centre,  with  slowing  of  the  heart,  and  has  a  direct  and  tonic 
effect  on  the  heart  muscle.  When  administered  sub- 
cutaneously  very  small  doses  produce  a  marked  vaso- 
constrictor effect. 

It  is  chiefly  used  locally  in  haemorrhage  and  in  catarrhal 
and  congestive  conditions.  Its  vaso-constrictor  action  is 
employed  also  to  intensify  the  effects  of  local  anaesthetics  by 
retarding  the  circulation  in  the  affected  part,  thus  hindering 
the  dilution  of  the  anaesthetic  by  too  rapid  absorption  in  the 
blood  stream. 

ADRENALINE  SUBSTITUTES.— Numerous  amines  have 
an  action  more  or  less  resembling  that  of  adrenaline 
(Barger  and  Dale,  J.  Physiol.  (1910),  41,  19).  Three,  all 
closely  related  to  adrenaline  in  structure,  have  been  re- 
commended as  substitutes  but  have  not  found  wide 
application. 

ARTERENAL  /-3  :  4-dihydroxy  -  phenyl  -  ethanol  -  amine, 
(OH)2C6H3'CH(OH)-CH2NH2,  m.p.  191°  (hydrochloride, 
m.p.  141°),  is  said  to  be  about  half  as  active  as 
/-adrenaline. 

HOMORENON  (w-ethylamino-3  :  4-dihydroxy -ace tophe- 
none)  (OH)2C6H3'CO'CH2-NirC2H6  affords  a  crystalline 
hydrochloride,  m.p.  260°,  and  it  has  a  much  weaker  action 
than  adrenaline. 


VASO-CONSTRICTORS  AND   VASO-DILATORS    223 

EPININE  (3  :  4-dihydroxy-phenyl-ethyl-methylamine) 
(OH)  2C6H3-CH2-CH2-NH-CH3 

M.p.  i88°-i89°  (Pyman,  Trans.  Chem.  Soc.  (1910),  97,  272), 
is  intermediate  in  action  between  the  two  former  bases. 

ETHYL  NITRITE— C2H5NO2.— Ethyl  nitrite  is  employed 
in  medicine  in  the  form  of  an  alcoholic  solution,  known  as 
"  Spiritus  ^Etheris  Nitrosi."  The  B.P.  requires  the  solution 
to  contain  i  -5  to  2'6  %  of  ethyl  nitrite,  and  the  U.  S.  P.  4-0  %. 

It  can  be  prepared  by  either  of  the  following  methods. 

(a)  Forty  parts  by  volume  of  sulphuric  acid  (sp.  gr.  1-84) 
are  added  to  120  parts  of  water,  followed,  after  cooling,  by 
a  mixture  of  85  vols.  of  alcohol  (90  %)  and  85  parts  of  water. 
The  mixture  is  cooled  to  o°,  when  a  filtered  solution  of  100 
parts  of  sodium  nitrite  in  280  parts  of  water  is  added  drop 
by  drop,  the  temperature  being  kept  below  +5°.     When  all 
has  been  added,  the  liquid  portion  is  decanted  from  crystals 
of  sodium  sulphate,  and  transferred  to  a  cooled  separator,  in 
which  the  ethyl  nitrite  layer  is  separated.    It  is  washed,  first 
with  20  parts  of  ice-cold  water,  then  with  15  parts  of  water 
containing  O'6  part  of  sodium  carbonate  (monohydrate), 
and  dried,  after  careful  separation,  by  agitation  with  3  parts 
of  anhydrous  potassium  carbonate.     It  is  then  mixed  with  a 
weighed  amount  of  alcohol  and  diluted  to  the  required 
strength. 

(b)  One   hundred  parts  by   volume   of   sulphuric   acid 
(1-84  sp.  gr.)  are  added  to  1000  vols.  of  alcohol  (90  %), 
followed  by  125  vols.  of  nitric  acid  (sp.  gr.  1-4),  with  cooling 
and  stirring.     One  hundred  parts  of  copper  turnings  are 
then  added  and  the  mixture  gently  distilled,  the  commencing 
temperature  being  77°.     The  receiver  contains  1000  vols. 
of  90  %  alcohol,  which  is  cooled  to  o°.     Distillation  is 
continued  until  the  volume  in  the  receiver  has  increased  to 
1600  parts ;    the  contents  of  the  still  are  then  allowed  to 
cool,  when  25  vols.  more  of  nitric  acid  are  added,  after  which 
distillation  is  resumed,  and  continued  until  a  further  100 
parts  of  distillate  have  been  collected. 

The  product  is  then  assayed  (see  below)  and  diluted  with 


224         ORGANIC  MEDICINAL  CHEMICALS 

alcohol  until  it  contains  2*66  %  by  weight  of  ethyl  nitrite 
(B.  P.). 

Spirit  of  nitrous  ether  B.  P.  has  a  sp.  gr.  of  o '823-0 -840 
at  15°.  When  freshly  prepared  it  is  neutral  in  reaction 
towards  litmus,  but  gradually  develops  acidity  on  keeping. 
This  instability  shows  itself  in  some  degree  under  all  con- 
ditions of  storage  and  is  accompanied  by  loss  of  ethyl 
nitrite. 

Ten  c.c.  of  the  spirit,  mixed  with  5  c.c.  of  normal  sodium 
hydroxide  solution  and  5  c.c.  of  water,  assumes  a  yellow 
colour  which  should  not  become  brown  within  12  hours 
(freedom  from  aldehydes). 

Ten  c.c.  should  not  require  more  than  0*2  c.c.  of  N/i 
alkali  for  neutralisation. 

Assay  :  A  quantity  of  about  30  grams  of  the  spirit, 
which  has  been  previously  shaken  with  0*5  gram  of  potassium 
bicarbonate,  is  transferred  to  a  graduated  100  c.c.  measuring 
flask,  and  is  accurately  weighed.  It  is  then  diluted  to  100  c.c. 
with  alcohol  (95  %)  and  thoroughly  mixed.  A  measured 
quantity  of  10  c.c.  of  this  solution  is  introduced  into  a 
nitrometer  filled  with  saturated  brine.  Ten  c.c.  of  10  % 
potassium  iodide  solution  are  introduced,  followed  by  10  c.c. 
of  N/i  sulphuric  acid.  The  volume  of  gas  evolved  is  read 
off  when  it  has  become  constant,  usually  within  30  to  60 
minutes.  The  number  of  c.c.  of  gas  is  multiplied  by  0-307, 
and  the  product  divided  by  one-tenth  of  the  original  weight 
of  the  ethyl  nitrite  solution  taken.  At  the  standard  temper- 
ature and  pressure  the  quotient  will  represent  the  percentage 
of  ethyl  nitrite  in  the  liquid. 

Ethyl  nitrite  solution  is  stimulant,  diuretic,  diaphoretic 
and  antipyretic.  It  is  used  in  dropsy  of  renal  origin,  and  in 
asthma,  angina  pectoris  and  dysmenorrhcea. 

AMYL  NITRITE  (Isoamyl  Nitrite)  C5HnONO.  117.— 
Amyl  nitrite  is  prepared  by  distilling  amyl  alcohol  with 
nitrous  acid.  Thirty  parts  of  the  mixture  of  isomeric  amyl 
alcohols,  obtained  by  fermentation,  distilling  between  127*7° 
and  132-2°,  are  dissolved  in  30  parts  of  concentrated  sulphuric 
acid.  To  the  cold  solution  are  added,  with  stirring,  26  parts 


VASO-CONSTRICTORS  AND   VASO-DILATORS    225 

of  potassium  nitrite  (or  21  parts  of  sodium  nitrite)  mixed 
with  15  parts  of  water.  The  mixture  is  then  slowly  heated, 
when  amyl  nitrite  distils  over.  The  distillate  is  washed, 
first  with  sodium  carbonate  solution,  then  with  sodium 
bisulphite,  finally  with  water,  dried  over  calcium  chloride, 
and  rectified.  The  U.  S.  P.  requires  a  content  of  about 
80  %  of  amyl  nitrite. 

By  another  method  (Ber.  (1886),  19,  915)  a  concentrated 
aqueous  solution  of  35  parts  of  sodium  nitrite  is  treated 
with  44  parts  of  amyl  alcohol,  and  the  mixture  cooled  to  o°. 
With  efficient  stirring  and  cooling  43  vols.  of  hydrochloric 
acid  (sp.  gr.  1-19)  are  added,  the  temperature  being  main- 
tained at  o°.  The  oil  is  then  separated,  washed,  dried  and 
distilled,  amyl  nitrite  passing  over  at  94°-98°.  Yield  53  parts. 

An  alternative  method  of  preparation  consists  in  dis- 
solving 30  parts  of  amyl  alcohol  in  30  parts  of  concentrated 
sulphuric  acid,  adding  6  parts  of  copper  turnings,  30  parts 
of  concentrated  nitric  acid,  and  15  parts  of  water,  and  dis- 
tilling the  mixture  as  above. 

Amyl  nitrite  is  a  pale  yellow  volatile  liquid.  The  British 
Pharmacopoeia  requires  that  70  %  should  distil  between  the 
temperatures  of  90°  and  100°.  Many  other  pharmacopoeias 
(Dutch,  Japanese,  Russian,  German,  etc.)  state  that  it  boils 
at  97°  to  99°.  To  meet  this  requirement  it  is  necessary  to 
start  from  an  amyl  alcohol  mixture  having  a  closer  range  of 
boiling  point  than  that  given  above. 

The  specific  gravity  at  I5'5°  should  be  0-870  to  0*880. 

Amyl  nitrite  is  insoluble  in  water  ;  soluble  in  alcohol, 
chloroform  and  ether. 

A  mixture  of  1*5  c.c.  silver  nitrate  solution,  1*5  c.c. 
alcohol  (pure),  and  a  few  drops  of  ammonia  solution,  when 
gently  warmed  with  i  c.c.  of  anryl  nitrite,  should  not  turn 
brown  or  black. 

It  must  not  become  turbid  when  cooled  to  o°  (absence 
of  water). 

Five  c.c.  should  not  decolourise  a  solution  containing 
i  c.c.  N./i  KOH,  10  c.c.  of  water,  and  a  drop  of  phenolphtha- 
lein,  when  shaken  with  it. 

i.  15 


226         ORGANIC  MEDICINAL   CHEMICALS 

Estimation  :  When  5  c.c.  of  a  5  %  solution  of  amyl 
nitrite  in  alcohol  (90  %)  is  shaken  intermittently  for  5 
minutes,  in  a  nitrometer  containing  saturated  brine  solution, 
with  5  c.c.  of  a  20  %  solution  of  potassium  iodide  and  5  c.c. 
of  10  %  sulphuric  acid,  and  the  liquid  in  the  two  limbs  of 
the  nitrometer  is  adjusted  to  the  same  level,  not  less  than 
30  c.c.  of  gas  (nitrogen),  adjusted  to  N.  T.  P.  should  be  yielded 
(B.P.).  The  number  of  c.c.  of  gas  multiplied  by  5  gives  the 
weight  in  milligrams  of  amyl  nitrite  present. 

Amyl  nitrite  is  an  antispasmodic,  and  a  restorative  in 
cardiac  failure  during  chloroform  or  nitrous  oxide  anaesthesia. 
It  is  much  used  in  angina  pectoris,  where  a  rapid  fall  of 
arterial  tension  is  required  ;  in  epilepsy,  neuralgia,  migraine, 
and  seasickness  ;  also  in  spasmodic  asthma  and  in  hepatic, 
intestinal  and  renal  colic. 

It  is  administered  by  inhalation  ;  and  internally,  dis- 
solved in  alcohol  and  diffused  through  water  by  the  aid  of 
tragacanth  powder.  In  cases  of  Bright's  disease,  where 
prolonged  administration  is  required,  it  is  advisable  to 
employ  an  amyl  nitrite  that  has  been  prepared  from  pure 
amyl  alcohol. 

NITROGLYCERIN  (Trinitrin,  Glonoin) 

CH2ONO2-CHONO2'CH2ONO2.     227. 

— As  the  preparation  of  nitroglycerin  on  the  commercial 
scale  is  dealt  with  in  a  book  on  "  Explosives  "  in  this  series, 
a  brief  account  only  will  here  be  given. 

Six  parts  of  a  mixture  of  nitric  acid  (1*5  sp.  gr.)  and 
oleum,  and  having  the  approximate  composition  H2SO4  58  % ; 
HNO3  41  % ;  H20 1*0  %,  are  placed  in  a  lead  vessel  provided 
with  cooling  coils,  and  are  agitated  by  compressed  air.  One 
part  of  glycerin  is  introduced,  through  an  aluminium  rose, 
in  the  form  of  a  fine  spray,  the  rate  of  addition  being  so 
regulated  that  the  temperature  is  maintained  at  about  22°. 
The  water  in  the  cooling  coils  is  maintained  under  a  slight 
vacuum,  so  that  in  case  of  leakage  through  corrosion  none 
can  enter  the  nitration  mixture.  A  modern  type  of  nitrator 
is  described  in  B.  P.  15893/1911. 


VASO-CONSTRICTORS  AND   VASO-DILATORS    227 

When  all  the  glycerin  has  been  added,  the  mixture  is 
cooled  to  15°.  The  nitroglycerin,  which  separates  as  a 
layer  on  the  surface  of  the  acid,  is  displaced  into  a  washer 
by  running  in,  at  the  bottom  of  the  vessel,  waste  acid  from 
a  previous  charge.  The  nitrator  is  allowed  to  remain  filled 
with  the  waste  acid  until  required  again  for  use.  Nitrogen 
oxides  evolved  during  the  operation  are  carried  away  to  a 
stoneware  condensing  tower  and  absorbed  in  water.  The 
nitroglycerin  is  washed,  in  wide  and  shallow  tanks,  thrice 
with  water  at  18°,  four  times  with  a  3^  %  solution  of 
sodium  carbonate,  and  finally  twice  with  water  at  30°. 

Nitroglycerin  is  a  colourless  or  pale  yellow  oil,  specific 
gravity  ig6.  It  is  very  slightly  soluble  in  water,  dissolves 
readily  in  alcohol  and  is  miscible  with  ether  or  chloroform. 
When  shaken  with  water  the  latter  should  not  acquire  an 
acid  reaction.  Nitroglycerin  explodes  with  great  violence 
on  percussion.  It  is  employed  in  medicine  in  the  form  of  a 
10  %  solution  in  alcohol. 

Nitroglycerin  is  a  vaso-dilator,  employed  chiefly  in  angina 
pectoris  associated  with  aortic  diseases.  It  reduces  arterial 
tension  in  Bright's  disease,  and  acts  as  a  diuretic  and 
diminishes  the  albuminuria.  Its  action  is  similar  to  that  of 
amyl  nitrite,  but  is  slower  and  more  prolonged.  It  is 
employed  also  in  spasmodic  asthma  and  in  headache  or 
neuralgia  if  associated  with  pallor. 

ERYTHROL  TETRANITRATE  (tetranitrin) 

CH2ONO2 

! 
(CHON02)2        302. 

I 
CH2ONO2 

— The  preparation  of  erythrol  tetranitrate   is  based  on  a 
method  given  by  Stenhouse  (Ann.  (1849),  7°>  22^)- 

One  part  of  powdered  erythrol  is  added,  with  good 
stirring  and  in  small  quantities  at  a  time,  to  strongly  cooled 
nitric  acid  (sp.  gr.  1-5),  4|  parts.  The  temperature  is  not 
allowed  to  rise  above  o°.  When  all  has  dissolved,  9  parts 


228         ORGANIC  MEDICINAL   CHEMICALS 

of  concentrated  sulphuric  acid  are  added,  and  the  mixture 
allowed  to  stand,  when  the  tetranitro  compound  crystallises 
out.  After  several  hours  it  is  filtered  off,  on  asbestos, 
washed  with  ice-cold  water  until  the  washings  are  free  from 
sulphate  ions,  and  recrystallised  from  hot  alcohol. 

Erythrol  tetranitrate  is  a  colourless  crystalline  solid. 
M.p.  61.  It  is  sparingly  soluble  in  water ;  readily  soluble 
in  alcohol.  The  solutions  should  be  quite  neutral.  It  is 
stable  if  kept  in  a  dark  and  cool  place,  but  if  exposed  to 
warmth  and  especially  sunlight  it  rapidly  decomposes. 
Care  should  be  exercised  in  handling  this  substance  as  it 
explodes  on  percussion. 

Tetranitrin  is  a  vaso- dilator  ;  it  is  comparable  in  action  to 
nitroglycerin,  having,  however,  a  less  marked  but  more  pro- 
longed activity. 

MANNITOL  HEXANITRATE  (hexanitrin) 

CH2ON02-(CHON02)4-CH2-ON02.     452. 

— One  part  of  finely  powdered  mannitol  is  gradually  treated, 
with  stirring,  with  5  parts  of  nitric  acid  (sp.  gr.  1-5).  When 
all  has  dissolved,  the  solution  is  cooled  to  o°  and  10  parts  of 
concentrated  sulphuric  acid  are  added.  After  standing  for 
an  hour  the  separated  crystals  of  mannitol  hexanitrate  are 
filtered  off,  and  washed,  first  with  cold  water,  then  with 
warm  sodium  carbonate  solution.  They  are  finally  re- 
crystallised  from  alcohol  (Sokolow,  Journ.  d.  Russ.  Chem. 
Ges.  1 1 , 136) .  According  to  Strecker  (Ann.  73, 62),  one  part 
of  powdered  mannitol  is  rubbed  with  just  sufficient  nitric 
acid  (1*5  sp.  gr.)  completely  to  dissolve  it.  The  solution  is 
then  treated  alternately  with  nitric  and  sulphuric  acids  until 
4j  parts  of  the  former  and  loj  parts  of  the  latter  have 
been  added.  A  hard  mass  of  crystals  is  obtained.  They 
are  filtered  off,  washed  with  cold  water,  partially  dried  and 
crystallised  from  alcohol. 

The  nitro-sulphuric  acid  mixture  affords,  when  diluted 
with  ice,  a  further  quantity  of  mannitol  hexanitrate. 

Mannitol  hexanitrate  crystallises  in  colourless  silky 
needles.  It  is  almost  insoluble  in  water,  is  fairly  soluble  in 


VASOCONSTRICTORS  AND   VASO-DILATORS    229 

alcohol,  and  readily  soluble  in  ether.  It  explodes  on  per- 
cussion, and  therefore  requires  to  be  handled  with  care. 
It  is  employed  as  a  vaso-dilator  in  a  similar  manner  to 
erythrol  tetranitrate.  Its  action  is  said  to  be  more  pro- 
longed, but  milder  than  that  of  erythrol  tetranitrate. 


SECTION  VIIL—  DIURETICS  AND  UEIC  ACID 
SOLVENTS 

NONE  of  the  drugs  available  for  increasing  the  flow  of  urine 
can  be  regarded  as  satisfactorily  meeting  the  requirements  of 
medical  practice.  Theobromine,  theophylline  and  caffeine 
are  the  substances  in  commonest  use  for  this  purpose. 

Since  these  are  derivatives  of  uric  acid  and  it  is  for  the 
elimination  of  uric  acid  that  such  drugs  are  most  frequently 
required,  the  objection  to  them  in  this  connection  is 
obvious. 

The  hormone  secreted  by  the  posterior  lobe  of  the 
pituitary  gland  exerts  a  very  marked  diuretic  action.  The 
chemical  nature  of  the  substance  so  secreted  is  not  yet 
determined,  and  when  this  is  achieved  it  is  not  improbable 
that  the  knowledge  so  acquired  will  materially  assist  the 
chemist  in  the  search  for  an  ideal  diuretic  substance. 

Of  drugs  which  act  as  solvents  of  uric  acid  piperazine 
and  atophan  have  given  greatest  satisfaction  ;  the  former  is 
a  solvent  in  vitro  for  uric  acid  but  does  not  appear  to  act 
satisfactorily  in  dissolving  uric  acid  gravel  and  calculi. 
Atophan  increases  the  amount  of  uric  acid  eliminated  by 
the  urine  in  a  manner  as  yet  unexplained. 

CAFFEINE  (1.3.7  trimethyl-xanthine) 

(1)        (6) 

CH3-N—  CO 

I  (2)    1(5)  (7)  /CH3 

COC—  N<(8)    +H20     212. 


1(3)    11(4)  (9)  ./^CH 

-N—  C—  1ST 


CH3 
—  Caffeine  is  manufactured  from  natural  sources  as  well  as 


DIURETICS  AND   URIC  ACID  SOLVENTS    231 

synthetically  ;  the  former  consist  of  soiled  tea  or  tea-dust 
and  the  by-product  from  the  preparation  of  "  caffeine-free  " 
coffee  extracts,  whilst  synthetically  it  is  obtained,  as  are  the 
closely  allied  compounds,  theobromine  and  theophylline,  from 
uric  acid,  by  the  following  reactions,  of  which  numerous 
modifications  have  been  devised. 


(i)    NH—  CO 

CO      C—  NH, 

I      ii       N 

tiH—  C—  NH/ 
Uric  acid. 

NH—  CO 

II 

CO      C-N 

->  II 

NH—  C  - 


,CH  c 

(CH3CO)2° 


/ 
(   C 


NH—  CO 


:0 — C— NH'COCH3 

\NH— C— NH-COCH3 

Diacetyl-diaraino-uracil. 

CH3— N— CO 


Methylation 


8-methyl  xanthine. 
CH—  N—  CO 


CH=> 


CH3—  N—  C—  N^ 

1.3.7.  8  -tetra  -methyl 
xanthine. 


CH—  N—  CO 


I       ||        \CH 
3—  N—  C—  N^ 


Trichlor-8-methyl  caffeine. 


(2)    NH—  CO 
|| 
CO     C—  NHX 

I      ii        >co 

NH—  C—  NH/ 
Uric  acid. 

CH3—  N—  CO 

I 


PH  T  I 

S2£->  CO  C  _  -N 

KOH  j       ||  CO 

CH3—  N—  C—  NH/ 
i  .  3-dimethyl-7-hydroxy-methylene  uric  acid. 


Caffeine. 

NH—  CO 

]|  CH2OH 

CO     C  -  N/ 

|       ii         >co 

NH—  C—  NH/ 

7-hydroxy  methylene  uric  acid. 

CH3—  N—  CO 


CH2OH  _  ^wr. 
Sn+HC1 


|       I  /CH8 

CO  C  -  N/ 


CO 


|       ||  > 

CH3—  N—  C—  NH/ 

1.3.  7-trimethyl  uric  acid. 


1.3.  7-trimethyl  uric  acid  is  also  obtained  by  the 
direct  methylation  of  uric  acid.  Treated  with  phosphorus 
oxychloride  it  gives  8-chloro-caffeine,  from  which  caffeine  is 
obtained  on  reduction. 


CH3— N— CO 

I       I 
CO  C— N 

I      II 
CHg—N— C-: 


CH3 
CC1 


HI 


Caffeine. 


232         ORGANIC  MEDICINAL   CHEMICALS 

Probably  the  first  method  only  is  employed  commercially 
for  making  caffeine  from  uric  acid.  Amongst  other  advan- 
tages it  possesses,  diacetyl-diamino-uracil,  one  of  the  inter- 
mediate compounds,  lends  itself  readily  to  conversion  into 
the  important  substance  theophyllin  (or  theocin).  The 
second  involves  two  more  operations,  and  includes  two 
reductions  with  expensive  reducing  agents. 

Caffeine  is  also  manufactured  by  Traube's  method,  by 
which  dimethyl  urea  (or  dimethyl  guanidine)  and  cyanacetic 
ester  constitute  the  starting  out  materials.  This  is  more 
economical  than  Fischer's  earlier  process,  which  started 
from  ethyl  malonate  and  dimethyl  urea. 

Traube's  synthesis  :  — 
(3)     NH—  CHS  COOEt  CH3N—  CO 

CO  +        CH2  ->  CO  CH2 

NH—  CH3  CN  CH3N—  G=NH 

i  .  3-dimethyl-4-amino-2  .  6-dioxy  pyrimidine. 

CHSN—  CO  CH8—  N—  CO 

COC=NOH       Reduction  r  COC-NH2 

CH3N    C=NH  CH8—  N—  C—  NH2 

i  .  3-dimethyl-2  .  6-dioxy 
4  .  5-diamino  pyrimidiue. 

I    H—  COOH 
CH8—  N—  CO 
Caffeine      <J^i-  CO  C—  NH'CHO 

NaOH 


I        j| 

3—  N—  C— 


CH3—  N—  C—  NH2 

Dimethyl  guanidine  can  be  used  in  place  of  dimethyl 
urea,  the  C=NH  group  being  subsequently  converted  into 
C=O  by  hydrolysis. 

Dimethyl  urea  is  prepared  by  distilling  potassium 
isocyanate  with  potassium  methyl-sulphate  and  treating  the 
resulting  methyl-isocyanate  with  methylamine,  or  with 
water. 

CH3N=C=0+CH3NH2 
2CH3NCO+H20    ->     C 


DIURETICS  AND   URIC  ACID  SOLVENTS    233 

Guanidine  is  now  made  from  calcium  cyanamide  via 
dicyano  diamide,  which  is  prepared  from  calcium  carbide 
CD.  R.  P.  222552),  and  is  methylated  by  means  of  dimethyl 
sulphate  (Arch.  Pharm.  (1909),  247,  466). 

Extraction  of  Caffeine  from  Tea. — Tea  dust  is  ex- 
tracted with  boiling  water.  The  extract  is  treated  with 
lead  acetate  solution  so  long  as  a  precipitate  is  formed,  and, 
after  filtration  and  removal  of  the  excess  of  lead  from  the 
filtrate,  is  evaporated  to  small  bulk.  On  cooling,  the 
caffeine  crystallises  out.  It  is  filtered  off,  and  purified  by 
recrystallisation  from  water,  employing  charcoal  as  a 
decolourising  agent.  Or  the  extract  may  be  evaporated 
to  dryness  on  a  film  evaporator  (Fig.  24)  and  the  dried 
material  extracted  with  ether  from  which  the  caffeine 
crystallises. 

Alternatively,  the  powdered  tea  is  mixed  with  one  quarter 
its  weight  of  slaked  lime,  and  exhausted  with  80  %  alcohol. 
The  extract  is  freed  from  alcohol  by  distillation,  the  residue 
is  diluted  with  water,  separated  from  fat,  concentrated,  and 
allowed  to  crystallise. 

For  recrystallising  caffeine,  alcohol,  benzene,  or  chloro- 
form may  be  used  in  place  of  water. 

Preparation   from   Uric   Acid  (D.   R.   P.    121224)  : 

NH— CO 

I          I' 
8-methyl-xanthine  CO     C— NHX 

I          II  >C-CH3 

NH— C N^ 

—One  part  of  uric  acid  is  boiled  with  10  parts  of  acetic 
anhydride  for  80  hours,  or  is  heated  under  pressure  at  180°- 
185°  with  5-6  parts  of  anhydride,  or  is  boiled  for  40-45  hours 
with  10  parts  of  acetic  anhydride  and  0*5  part  of  pyridine 
at  atmospheric  pressure.  After  cooling,  the  product  is 
filtered  off.  It  is  boiled  with  water,  in  which  any  diacetyl 
diamino-uracil  which  has  not  been  converted  into  8-methyl- 
xanthine  will  dissolve.  After  filtration  the  insoluble  8- 
methyl-xanthine  is  washed  with  alcohol. 


234         ORGANIC  MEDICINAL  CHEMICALS 


DIURETICS  AND   URIC  ACID  SOLVENTS    235 

1.3.7. 8-tetm-methyl-xanthine  (8-methyl-caffeine). 

CH3— N— C 

I       I          /CH3 

CO  C— N< 


\^^J   V^ **\ 

I      II         >C-€H3 

_N_C_]Sr 


—  Ten  parts  of  8-methyl-xan  thine  are  dissolved  in  10-5  vols. 
of  2N.  sodium  hydroxide,  mixed  with  12  parts  of  methyl 
chloride  and  heated  in  an  antoclave  for  7  hours  at  80°. 
On  cooling,  the  8-methyl-caffeine  crystallises  out  in  the  form 
of  fine  needles. 

It  dissolves  in  i'6  parts  of  boiling  water,  is  easily  soluble 
in  hot  chloroform,  and  fairly  readily  soluble  in  alcohol, 
benzene,  acetone,  and  ethyl  acetate. 

CH3—  N—  CO 

I       I         /CH3 
8-trickloromethyl-caffeine  CO  C  —  N<T 

I      II         >C-CC13 
CH3—  N—  C—  N^ 

(D.  R.  P.  146714).  —  One  hundred  parts  of  8-methyl-caffeine 
are  dissolved  in  500  vols.  of  chloroform  and  the  solution  is 
cooled  to  o°.  At  this  temperature  are  added,  with  con- 
stant stirring,  270  parts  of  sulphuryl  chloride  (SO2C12). 
When  the  addition  is  complete,  and  hydrogen  chloride  has 
ceased  to  be  evolved,  the  chloroform  is  distilled  off  and  the 
product  purified  by  recrystallisation  from  ethyl  acetate. 

Alternatively,  direct  chlorination  of  the  chloroform  solu- 
tion can  be  effected.  8-trichloro-methyl-caffeine  melts  at 
i82°-i84°. 

Caffeine  from  8-trichloro-methyl-caffeine  (D.  R.  P. 
151133).  —  One  part  of  8-trichloro-methyl-caffeine  is  boiled 
under  reflux  with  10  parts  of  water  until  the  acidity  required 
by  the  following  equation  is  developed  :  — 


The  solution  is  then  evaporated  and  the  caffeine,  which 


236         ORGANIC  MEDICINAL   CHEMICALS 

crystallises  out  after  cooling,  filtered  off,  washed,  and  re- 
crystallised. 

Alternatively,  one  part  of  dry  8-trichloro-methyl-caffeine 
is  mixed  with  one  part  of  anhydrous  oxalic  acid  and  the 
mixture  heated  for  several  hours  at  I5o°-i8o°.  After 
cooling,  the  reaction  product  is  powdered,  dissolved  in 
chloroform,  filtered  and  distilled  to  dryness.  The  residue 
is  recrystallised  from  ethyl  acetate. 

Preparation  from  Dimethyl -urea: 

Ethyl  cyanacetate  CN— CH2— COOC2H5  (Amer.  Jour,  of 
Sci.  (1908),  26,  275). — Two  hundred  parts  of  monochloracetic 
acid  are  treated  with  50  parts  of  water  and  300  parts  of  sodium 
carbonate  cryst.  with  stirring.  The  reaction  is  endothermic, 
causing  the  mass  to  freeze,  and  may  be  hastened  by  circu- 
lating water  at  atmospheric  temperature  round  the  vessel. 
The  solution  of  sodium  chloracetate  is  then  poured  as  quickly 
as  possible  into  a  solution  of  165  parts  of  potassium  cyanide 
(98  %)  in  250  parts  of  water,  which  is  maintained  at  a 
temperature  of  ioo°-no°.  After  the  addition  is  complete  the 
solution  is  boiled  for  5  minutes  to  complete  the  reaction. 
After  cooling,  the  solution  is  made  faintly  acid  with  sulphuric 
acid,  employing  logwood  paper  as  the  indicator.  The  precipi- 
tated salts,  sodium  and  potassium  sulphates  and  chlorides,  are 
filtered  off,  and  the  filtrate,  which  contains  cyanacetic  acid, 
is  concentrated  as  far  as  possible  under  reduced  pressure 
at  70°-8o°.  The  salts  are  washed  with  300  vols.  of  96  % 
alcohol  and  filtered,  when  the  alcoholic  filtrate  is  mixed 
with  the  cyanacetic  acid  residue.  The  mixture  is  well 
agitated,  filtered,  and  the  insoluble  matter  washed  with  100 
parts  of  alcohol.  The  combined  alcoholic  solutions  are 
then  freed  from  solvent  by  distillation  under  reduced 
pressure  at  5o°-6o°. 

The  residue  consists  chiefly  of  cyanacetic  acid,  with 
some  ester  and  a  little  alkali  cyanacetate.  Pure  cyanacetic 
acid  may  be  obtained  by  extraction  with  hot  chloroform, 
from  which  it  crystallises  well.  For  the  preparation  of  the 
ester  the  crude  acid  is  mixed  with  100  vols.  of  absolute 
alcohol  and  5  vols.  of  sulphuric  acid  (1*84).  The  mass  is 


DIURETICS  AND   URIC  ACID  SOLVENTS    237 

esterified  by  heating  the  mixture  to  boiling  and  passing 
through  it,  during  2^-3  hours,  the  vapour  of  500  vols.  of 
absolute  alcohol.  The  ester  is  then  purified  by  extraction 
in  the'  usual  way,  washing,  and  rectifying  in  vacuo. 

The  yield  is  stated  to  be  92-93  %. 

Condensation  of  Ethyl-cyanacetate  and  Dimethyl-urea 
CH3— N— CO 

I     ! 

to  CO  CH  Twenty   parts  each  of  sodamide 

CH3— N— C— NH2 

and  dry  dimethyl-urea  are  thoroughly  mixed,  and  treated 
with  20  parts  of  xylene.  With  efficient  stirring  and  good 
cooling  are  added  20  parts  of  ethyl-cyanacetate.  After 
the  main  reaction  is  over,  the  mixture  is  heated  for  several 
hours  at  ioo°-i20°. 

After  cooling,  the  product  is  carefully  treated  with  water, 
the  xylene  removed,  and  the  i  .  3-dimethyl-2  .  6-dioxy-4- 
amino-pyrimidine  precipitated  with  acid  (D.  R.  P.  165561). 
Instead  of  sodamide,  sodium  in  absolute  alcohol  may  be 
used  (D.  R.  P.  134984),  or  sodium  in  xylene  (D.  R.  P.  165562). 

i .  ^-dimethyl-2  . b-dioxy-^-amino-^-isonitroso-pyrimidine 
CH3— N— C=O 

I       I 
CO  C— NOH 

I       II 
CH3— N— C— NH2 

The  above  compound  is  dissolved  in  hot  water  containing 
the  theoretically  necessary  quantity  (i  mol.)  of  sodium  nitrite. 
Dilute  acetic  acid  is  then  added,  when  the  solution  becomes 
red-coloured  and  the  isonitroso  derivative  commences  to 
crystallise  out.  After  standing  for  about  24  hours  crystal- 
lisation is  complete  and  the  liquor  is  almost  colourless  (Ber. 
(1900),  3052). 

Reduction    to    i .  3-dimethyl-2  .  6-dioxy-4  .  5-dia- 
CH3— N— C=O 

I       I 
mino-pyrimidine       CO  C — NH2      According  to  Traube's 

I     I! 

CH3— N— C— 


238         ORGANIC  MEDICINAL   CHEMICALS 

original  method,  this  was  carried  out  by  boiling  with 
ammonium  sulphide  solution.  It  is  stated  by  D.  R.  P. 
161493  to  be  better  effected  by  the  following  procedure. 

Five  parts  of  the  isonitroso  compound  are  rubbed  up 
with  50  to  100  parts  of  20  %  sulphuric  acid,  and  the  mixture 
gradually  treated  with  5  parts  of  zinc  dust.  The  temper- 
ature is  maintained,  by  cooling,  at  between  20°  and  30°. 
The  red  colour  of  the  isonitroso  body  gradually  disappears, 
whilst  white  crystals  of  the  sulphate  separate.  Water  is 
added  after  the  reduction  is  finished,  the  mixture  is  filtered 
and  the  zinc  residue  washed  thoroughly  with  hot  water. 
The  combined  filtrates  are  freed  from  zinc,  by  treatment 
with  sodium  carbonate,  and  evaporated  to  dryness.  The 
base  is  extracted  from  the  residue  with  chloroform  or  some 
other  suitable  solvent.  M.p.  209°.  It  is  stated  that  this 
reduction  can  also  be  effected  with  iron,  and  according  to 
D.  R.  P.  166267  it  is  carried  out  electrolytically. 

i  .  3 -dimethyl -2  .  6-dioxy-4-amino~5-formylamino  pyri- 

-C— NH— CHO 
midine        \\  The  formyl  compound  of  the  base 

— C— NH2 

thus  obtained  is  prepared  by  digesting  the  diamine  with 
several  times  its  weight  of  90  per  cent,  formic  acid  at  its 
boiling  point.  The  resulting  substance  melts  at  252°.  If 
necessary  it  is  purified  by  recrystallisation  from  water.  It 
is  dried  before  further  treatment. 
CH3N— CO 

I       I 
Conversion    of  CO  C — NH — CHO     into  caffeine — 

I      II 
CH3N— C— NH2 

The  completely  dry  formyl  compound  is  dissolved  in 
absolute  alcohol  containing  one  molecular  equivalent  of 
sodium  ethylate,  the  quantity  of  alcohol  employed  being 
such  that  the  resulting  sodium  salt  remains  dissolved  in  the 
hot  solution ;  a  slight  excess  of  methyl  iodide  is  added  and 
the  mixture  refluxed  for  several  hours.  On  then  con- 
centrating the  solution  caffeine  separates  in  long  silky 
needles. 


DIURETICS  AND   URIC  ACID  SOLVENTS    239 

By  anothef  series  of  reactions  urea  is  condensed  with 
cyanacetic  ester  to  2 . 6-dioxy-4-aminopyrimidine  (B.  P. 
22126/1904),  which  is  converted  first  into  the  isonitroso, 
then  into  the  diamido  compound.  This,  on  methylation, 
(D.  R.  P.  148208)  yields  i .  3-dimethyl-2  .  6-dioxy-4-amino- 
5-formylamino  pyrimidine  (see  above). 

Caffeine  crystallises  with  one  molecule  of  water  in  fine, 
colourless,  silky  acicular  crystals,  which  possess  a  bitter  taste. 

It  dissolves  in  one  part  of  boiling,  and  in  68  parts  of 
cold,  water  ;  in  7  of  chloroform  and  in  40  of  alcohol  (90  %) . 
In  ether  it  is  only  sparingly  soluble  (i  in  400). 

Caffeine  loses  its  water  of  crystallisation  at  100°  and  then 
melts  at  I32°-I33°.  It  dissolves  without  colour  in  sulphuric 
and  nitric  acids.  The  aqueous  solution  should  be  neutral 
to  litmus  and  should  give  no  precipitate  with  mercuric 
potassium  iodide  solution.  The  cold  saturated  aqueous 
solution  should  not  become  turbid  with  chlorine  water,  nor 
become  coloured  on  the  addition  of  ammonia  solution. 

Caffeine^  acts  on  the  kidneys  (increasing  the  flow  of  urine), 
and  on  the  muscles  and  heart ;  also  on  the  central  nervous 
system.  The  stimulant  action  of  tea  and  coffee  is  due  to 
it.  It  is  employed  in  medicine  as  a  heart  tonic  and  diuretic. 
It  is  frequently  given  in  the  form  of  caffeine  citrate,  a  mixture 
with  citric  acid  which  is  soluble  in  32  parts  of  water,  or  in 
combination  with  sodium  salicylate  or  sodium  benzoate, 
both  of  which  increase  its  solubility  in  water. 

Theophylline  or  Theocine.     (i .  3-di-methyl-xanthine). 

CH3N— CO 

I      I 

CO  C— NHX 

|      |]  ^CH+HsO     198. 

CH3N— C ST 

Theophylline  occurs  naturally  in  small  amounts  in  the  tea 
plant,  Camellia  Thea,  in  association  with  caffeine.  That 
used  in  medicine,  however,  is  exclusively  prepared  syntheti- 
cally, from  uric  acid,  urea,  guanidine,  or  their  methylated 
derivatives. 


240        ORGANIC  MEDICINAL   CHEMICALS 

(i)  From  uric  acid  :  1.3.7.  8-tetra-methyl-xanthiue 
(see  Caffeine) ,  on  exhaustive  chlorination,  gives  a  tetrachlor- 
tetramethyl-xanthine,  which  affords  theophylline  on  hydro- 
lysis : — 


CH3N— C=O  CH3— N— C=O 

I      I  /CH3  |       |          yCH2Cl 

CO  C— N<  2>  CO  C— N< 

1      ||         \C— CH,  |       ||  C— CC1. 

CH3— N— C— N^  CH3— N 

Tetraraethyl-xanthinc. 


8—  N—  C=0 


I      I  CH 

CH8—  N—  C—  N^ 
Theophylline. 

(2)  From  diacetyl-diamino-uracil,  by  the  following 
steps  :  — 

NH—  CO  NH—  CO  NH—  CO 

CO     C—  NH—  COCH3  ->  CO    C—  NH2     £££2JL>    CO    C—  NH-CHO 

NH—  C—  NH—  COCH8       NH—  C—  NH2  NH—  C—  NH2 

Diacetyl-diamino-uracil  2  ,6-dioxy-4.5-diamino 

(See  Caffeine).  pyrimidine.  |  Methylation. 

CH3—  N—  CO 
KOH 
Theophylline    <-  -  CO  C—  NH—  CHO 

f       II 
CH3—  N—  C—  NH2 

i  .  3-dimethyl-4-amino-5-formylamido- 
'    2  .  6-dioxy-pyrimidine. 

(3)  From  dimethyl  urea  and  cyanacetic  ester.  —  The 

procedure  is  the  same  as  in  the  case  of  caffeine,  except  that 
the  methylating  agent  is  omitted  in  the  final  stage  ;  the 
conversion  of  1.3-  dimethyl  -  4  -  amino  -  5  -  f  ormy  lamido  -2.6- 
dioxy-pyrimidine  into  theophylline  being  effected  with 
potash. 

The  same  compound  is  obtained  as  stated  under 
Caffeine,  p.  239,  by  condensing  urea  with  cyanacetic  ester 
and  methylating  the  4-amino-5-formylamido-2  .  6-dioxy 
pyrimidine. 


DIURETICS  AND   URIC  ACID  SOLVENTS     241 

Method  I. 

Chlorination  0/1.3.7.  8-tetramethyl-xanthine  to  1:3- 
dimethyl-j-dichloromethyl-S-trichloromethyl-xanthine 

CH3—  N—  CO 

I      I  /CH2C1 

CO  C—  N<( 

I     'II        >C-CC13 
CH3—  N—  C—  £T 

Two  methods  of  procedure  are  given  in  D.  R.  P.  146715. 

(a)  One  part  of  tetramethyl-xanthine  (8-methyl-caffeine) 
is  dissolved  in  8  parts  of  nitrobenzene,  heated  at  9O°-ioo°, 
and  chlorinated  until  no  more  chlorine  is  absorbed.     Chlorine 
in  solution  is  removed  by  a  current  of  air,  and  the  nitro- 
benzene is  distilled  off  in  vacuo,  the  product  being  recrystal- 
lised  from  hot  alcohol.     It  melts  at  2O4°-205°. 

(b)  Ten  parts  of  8-methyl-caffeine  are  suspended  in  50 
parts  of  nitrobenzene  containing  a  trace  of  iodine,  and  36 
parts  of  sulphuryl  chloride  are  gradually  added,  with  stirring. 
After  a  short  time  the  suspended  solid  dissolves,  heat  being 
evolved.     The  solution  is  allowed  to  remain  at  room  temper- 
ature for  several  hours,  after  which  it  is  heated  for  two  hours 
at  100°.     The  nitrobenzene  is  removed  by  steam-distilla- 
tion.    After  cooling,  the  solid  product  is  filtered  off  and 
purified  by  recrystallisation  from  alcohol. 

Conversion  of  tetrachloro-8-methyl-xanthine  into  Theo- 
phylline  (D.  R.  P.  151133).  —  One  part  of  the  tetrachloro 
compound  is  boiled  under  a  reflux  condenser  with  10  parts 
of  water  until  no  more  formaldehyde  is  evolved,  and  until 
the  acidity  of  the  solution  has  increased  in  accordance  with 
the  equation— 


The    acidity   is    neutralised  with    alkali,  and,  on    cooling, 
theophylline  crystallises  out.     The   yield   is   stated   to   be 
quantitative. 
i.  16 


242         ORGANIC  MEDICINAL  CHEMICALS 

Method  II. 

NH—CO 

I          I 
4  .  ^-diacetyl-diamino-uracil  CO     C — NH— COCH3 

I          II 

NH— C— NH— COCH3 

(D.  R.  P.  126797). — Ten  parts  of  uric  acid  are  boiled  for 
15  hours  with  30  parts  of  acetic  anhydride  and  5  parts  of 
pyridine.  The  solid  reaction-product  is  filtered  off  and 
boiled  with  30  parts  of  water.  The  diacetyl-diamino-uracil 
passes  into  solution;  8-methyl-xanthine  remains  undissolved, 
and  is  filtered  off.  The  filtrate  is  concentrated,  and  on 
cooling,  the  desired  product  crystallises  out  in  colourless 
needles. 

NH— CO 

I         I 
4  .  $-diamino-2  .  6-dioxy-pyrimidine  CO    C — NH2 

I         II 

NH— C— NH2 

Fifteen  parts  of  diacetyl-diamino-uracil  are  boiled  gently  for 
15  minutes  with  100  volumes  of  50  %  caustic  alkali  solution. 
After  cooling,  the  clear  solution  is  diluted  with  300  vols.  of 
water  and  treated  with  an  excess  of  sulphuric  acid,  when  the 
sparingly  soluble  sulphate  of  4 .  5-diamino-2  . 6-dioxy-pyrimi- 
dine is  precipitated. 

4-amino-5-formylamido-2  .  6-dioxy-pyrimidine 

NH— CO 

I         I 
CO      C— NH— CHO 

I         II 
NH— C— NH2 

The  sulphate,  after  being  dried,  is  mixed  with  one  mole- 
cular equivalent  of  sodium  formate  and  boiled  with  10-15 
parts  by  weight  of  90  per  cent,  formic  acid.  Solution  first 
occurs,  followed  by  the  gradual  formation  of  a  precipitate. 
After  cooling  and  dilution  with  water  the  product  is  filtered 
off,  and  purified  by  recrystallisation  from  water,  or  by  dis- 
solving in  dilute  alkali  and  reprecipitating  with  acid. 


DIURETICS  AND   URIC  ACID  SOLVENTS    243 

1.3-  dimethyl  -  4  -  amino  -  5  -formylamido  -2.6-  dioxy  - 
CH3— N— C 

I      I 
pynmidine          CO  C—NH—CHO.— Eighty-five  parts  of  the 

I       II 
CH3— N— C— NH2 

monoformyl  compound  are  dissolved  in  1050  parts  of  normal 
caustic  soda  and  300  parts  of  water,  and  treated,  at  30°-4O°, 
with  efficient  agitation,  with  160  parts  of  methyl  iodide. 
When  this  has  for  the  most  part  disappeared,  the  reaction 
mixture  is  acidified  with  acetic  acid  and  evaporated  to 
small  bulk.  The  dimethylated  body,  which  crystallises  out 
on  cooling,  is  purified  by  recrystallisation  from  water 
(D.  R.  P.  148208). 

CH3N— CO 

I      I 
Conversion    of       CO  C— NH— CHO      into  Theophylline 

I      II 
CH3— N— C— NH2 

(D.  R.  P.  138444). — Ten  parts  of  the  dimethylated  mono- 
formyl compound  are  warmed  at  90°-ioo°  with  a  mixture  of 
10  parts  of  30  %  caustic  soda  and  100  parts  of  water.  After 
cooling,  the  solution  is  saturated  with  salt,  or  with  caustic 
soda,  when  the  sodium  salt  of  theophylline  crystallises  out. 
After  filtration  the  base  is  obtained  from  it  by  neutralisa- 
tion with  acid,  and  is  purified  by  recrystallisation  from  water. 
Alternatively,  a  solution  of  3  %  alcoholic  potash  (100 
parts)  or  of  potassium  (2*1  parts)  in  alcohol  (100  parts)  may 
be  employed.  In  these  cases  the  potassium  salt  of  theo- 
phylline crystallises  out  on  cooling. 

Method  III. 

From  Urea  and  Cyanacetic  Ester. — Preparation  of  4-amino- 
2 . 6-dioxy-pyrimidine 

NH— CO 

I         I 
CO— CH 

I         II 
NH— C— NH2 


244         ORGANIC  MEDICINAL  CHEMICALS 

Cyanacetic  ester,  113  parts,  is  dissolved  in  2260  parts  of 
absolute  alcohol  containing  46  parts  of  sodium.  Urea,  58 
parts,  is  then  added  and  the  mixture  boiled  under  reflux  for 
several  hours.  The  solution  is  then  neutralised,  the  alcohol 
distilled  off  and  the  residue  dissolved  in  water.  The  base  is 
precipitated  by  addition  of  acetic  acid  and  is  filtered  off. 
Sodium  or  sodamide  in  xylene  may  be  used  instead  of  sodium 
in  alcohol. 

The  conversion  of  this  compound  successively  into  the 

_C— NOH  -C— NH2 

iso-nitroso     ||  ,  diamino  ||  ,  and  f ormyldiamino 

-C— NH2  -C— NH2 

-C— NH— CHO 

||  compounds    is   performed    in    the    manner 

— C— NH2 

described  under  caffeine  for  the  i .  3 -dimethyl  derivative 
(p.  237).  The  methylation  of  the  last-named  body  and  the 
conversion  of  the  dimethyl  compound  into  theophylline  have 
been  described  above. 

Theophylline  forms  colourless  crystalline  needles  con- 
taining one  molecule  of  water,  which  is  lost  at  110°.  The 
anhydrous  substance  melts  at  268°.  It  is  soluble  in  190 
parts  of  cold  water,  and  in  80  parts  of  90  %  alcohol.  It 
dissolves  readily  in  ammonia  and  alkalis. 

Theophylline  is  used  as  a  diuretic,  mostly  in  the  form  of  a 
double  compound  of  its  sodium  salt  with  sodium  acetate.  It 
is  indicated  in  all  forms  of  dropsy  in  which  the  functions  of 
the  kidneys  are  not  too  seriously  impaired  by  the  disease. 
Theophylline  is  a  less  powerful  stimulant  than  caffeine,  but  is 
more  active  as  a  diuretic  than  either  caffeine  or  theobromine. 

THEOBROMINE  (3  .  7-dimethyl-xanthine) 

NH—  C=O 
I         I  /CH3 

CO     C— N<  1 80. 

I         II        >CH 
.CH3N C— W 

—Theobromine  is  contained  in  the  seeds,  both  in  the  shells 
and  the  endocarp,  of  the  cocoa  plant,  Theobroma  Cacao,  from 


DIURETICS  AND    URIC  ACID  SOLVENTS    245 

which  it  is  extracted  commercially.  It  is  probable  that  the 
entire  present  demand  is,  or  could  be,  economically  met  from 
this  natural  source. 

Extraction  from  Cocoa  Beans. — This  is  effected  in 
essentially  the  same  way  as  has  been  described  for  caffeine. 
Cocoa  beans,  which  contain  from  i  to  2  per  cent,  of  the 
alkaloid,  are  pressed  as  free  as  possible  from  fat,  ground  to  a 
fine  powder,  mixed  with  one-half  their  weight  of  sifted  slaked 
lime,  and  exhausted  with  80  %  alcohol.  The  extract  is 
acidified  with  hydrochloric  acid  and  the  alcohol  removed  by 
distillation.  The  residue  is  diluted  with  water,  freed  from 
fat,  concentrated  to  small  bulk,  and  made  alkaline  with 
ammonia,  whereby  the  theobromine  is  precipitated.  It  is 
filtered  oft  and  purified  by  recrystallisation  from  boiling 
water,  or  from  80  %  alcohol. 

Theobromine  can  be  synthesised,  however,  by  modifica- 
tions of  the  methods  that  have  been  described  under  Caffeine 
and  Theophylline.  The  starting  point  may  be  either  uric 
acid,  urea  or  monomethylated  urea,  or  guanidine. 

A  few  examples  are  given  : — 

From  Uric  Acid — 
(i) 

NH— CO  NH— CO  NH— CO 

II  II  POC13          I        | 

CO      C— NH,         Methylation.  CO      C— NHV         -»        CO     C— NH, 
I      II  >CO         "*  |       II  >co  |      II  XCC1 

NH— C— NH/  CH8N— C— NH/  CH8N— C— N^^ 

Uric  acid.  /  3-methyl  uric  acid. 

NH— CO 

Methylation.          |        |  /CH8       m 

-»  co  c— N<       4: 

I       ||  ;>CC1     Theo- 

^  CH8N— C— N^         bromfa. 

(2) 

NH— CO  NH— CO 

I      |               XH2OH     Sn+  |      |                CH3 

CO    C— N^                      ^.  CO    C— N" 

I      II          "~/CO  I     || 

CH3N-C— NH  '•  CH3N— C— NH 

3-methyl-7-oxymethylene  uric  acid.  3  .  7-dimethyl  uric  acid* 
(Also  by  methylatipn  of  7-oxyme- 
tbylene  uric  acid). 

NH— CO 


CO      C— N-( 
CH3N- 


POC13          CO     C_N^-CH3       HL     Theobromine> 


246 


ORGANIC  MEDICINAL  CHEMICALS 


From  Methyl,  or  Methylacetyl,  Urea  (Traube) 


(3)      HN— COCH3 
CO 

CHSNH 

Methyl-acetyl  urea. 


HN—CO 

>        CO  C— NOH 

I      II 
CH8N— C— NH2 


COOEt 
CH2 


HN—CO 

CO  CH 

I       II 

CH3N—  C—  NH2 
3-methyl-4-amino 
pyrimidine. 


HN—CO 

HN—CO 

1      I 
CO  C—  NH2      • 

->          CO  C—  NH—  CHO 

1      II 
CH3N—  C—  NH2 

CHSN—  C—  NH2 

3-methyl  4.5-diamino 
pyrimidine. 

1 

HN—CO 

Theobromine. 


CHSN—  C  -- 

3-methyl-xanthine. 


Of  these  the  only  one  that  will  be  given  in  detail  is  that 
via  hydroxymethylene  uric  acid,  of  which  an  example  has 
not  previously  been  furnished.  It  is  not  intended  to  imply, 
however,  that  this  would  be  the  most  economical  method  of 
synthetically  preparing  theobromine. 

Preparation  from  Uric  Acid 
7  '-hydroxymethylene  uric  acid 


NH— CO 

I          I 
CO     C- 

I        !l 

NH— C— NH 


-N< 


,CH2OH 


+H2O  (E.  P.  20447/1898). 


— One  part  of  uric  acid  is  dissolved,  by  the  aid  of  gentle 
warmth,  in  15  parts  of  water  and  i  part  (z\  mols.)  of  80  % 
caustic  potash.  The  solution  is  cooled,  mixed  with  i  '6  parts  of 
40  %  formaldehyde,  and  allowed  to  stand  for  about  24  hours. 
It  is  then  acidified  with  hydrochloric  acid,  agitated  with 
charcoal  and  quickly  filtered.  On  standing,  oxymethylene 
uric  acid  crystallises  out.  It  is  filtered  off,  washed  with 
alcohol  and  dried. 


DIURETICS  AND   URIC  ACID,  SOLVENTS    247 
^-methyl-j-oxymethylene-uric  acid 

NH— CO 

|      |  XCH2OH 

CO   C N< 

I      II  >CO 

CH3— N— C— NHX 

(B.  P.  3300/1899). 

Fifteen  parts  of  7-0x7  me  thy  lene  uric  acid  are  dissolved  in 
50  parts  of  twice  normal  potassium  hydroxide  solution  (i£ 
mols.)  and  50  parts  of  water.  Methyl  iodide,  13  parts  by 
volume,  is  added  and  the  mixture  heated  in  an  autoclave  for 
2  hours  at  8o°-90°,  with  stirring.  On  cooling,  some  3-methyl- 
uric  acid  crystallises  out.  This  is  separated  and  converted 
into  3-methyl-7-oxymethylene  uric  acid  by  treatment  with 
formaldehyde.  The  filtrate  is  evaporated  in  vacuo,  and  on 
neutralisation  3-methyl-7-oxymethylene  uric  acid  separates, 
and  is  collected. 

It  is  stated  that  the  same  product  is  obtained  when  i 
part  of  potassium  urate,  5*5  parts  of  40  %  formaldehyde, 
7-5  parts  (by  vol.)  of  methyl  iodide,  and  7-8  parts  of  water 
are  heated  together  in  an  autoclave  at  90°  for  2  hours, 

3  . 7 -dimethyl-uric  acid 

NH— CO 

I      I  /CH3 

CO  C N< 

I    II        >co 

CH3N— C— NIT 

(E.  P.  1678/1899). 

One  part  of  3-methyl-7-oxymethylene  uric  acid  is  dis- 
solved in  8  parts  of  concentrated  hydrochloric  acid,  cooled 
to,  and  maintained  at,  o°,  treated  with  5  to  6  parts  of 
granulated  tin,  and  stirred.  When  the  evolution  of  hydrogen 
has  become  sluggish,  after  about  20  hours,  the  reaction  is 
accelerated  by  the  introduction  of  gaseotis  hydrogen  chloride. 
After  about  40  hours  any  undissolved  tin  is  separated  and 
the  liquid  is  diluted  with  water,  when  3.7-dimethyl  uric  acid 


248         ORGANIC  MEDICINAL   CHEMICALS 

is  precipitated.     It  is  filtered  off  and  purified  by  solution  in 
ammonia,  treatment  with  charcoal,  and  reprecipitation. 
3 .  j-dimethyl-chloroxanthine  (chlorotheobromine) 

NH— CO 

I      I         /CH3 
CO   C— N< 

I      II        >CC1 
CH3N— C— N^ 

(see  E.  P.  5949A898). 

One  part  of  anhydrous  3.7-dimethyl  uric  acid  is  added  to 
5  parts  of  phosphorus  oxychloride,  and  the  mixture  heated, 
with  stirring,  at  I30°-i40°  for  3-4  hours.  The  excess  of 
POC13  is  then  distilled  off,  and  the  residue  dissolved  in  5 
parts  of  alcohol,  boiled  for  2-3  hours  and  allowed  to  cool. 
Chlorotheobromine  crystallises  out  on  cooling,  a  further 
portion  being  obtained  by  evaporation  of  the  solvent  from 
the  filtrate.  It  is  purified  by  solution  in  dilute  alkali,  and 
reprecipitation  after  decolourisation  with  charcoal. 

Theobromine  from  chlorotheobromine  (E.  P.  5949/ 
1898). — One  part  of  chlorotheobromine  is  heated  with  J  part 
of  phosphonium  iodide  and  8  parts  of  hydriodic  acid  (sp.  gr. 
1*96).  After  15-20  minutes  a  clear  solution  is  obtained. 
This  is  distilled  to  dryness,  the  residue  treated  with  water, 
and  the  solution  neutralised.  The  theobromine  is  filtered 
off  and  recrystallised  from  boiling  water. 

Theobromine  is  a  white  crystalline  powder,  which 
sublimes  without  melting  at  290°.  It  is  soluble  in  1700 
parts  of  cold  water,  or  in  5000  parts  of  alcohol  (90  %).  It 
dissolves  in  both  acids  and  alkali. 

Its  physiological  action  resembles  that  of  caffeine,  but  it 
is  without  action  on  the  central  nervous  system. 

Theobromine  is  employed  medicinally  as  a  diuretic  and 
cardiac  stimulant,  and  is  usually  administered  in  the  form 
of  the  soluble  double  compound  of  its  sodium  salt  with 
sodium  salicylate  (diuretin).  Another  soluble  derivative  is 
urocitral  (theobromine  sodium  citrate). 

PIPERAZINE — ] 


DIURETICS  AND   URIC  ACID  SOLVENTS    249 

86.  —  Piperazine  is  manufactured  according  to  the  following 
reactions.  Diphenyl-piperazine  is  first  prepared  by  treating 
ethylene  dibromide  with  aniline  in  the  presence  of  an  alkali  : 

2C2H4Br2+2C6H5NH2+2Na2C03 


This  is  converted  into  its  dinitroso  compound  or  into  a 
dinitro-disulphonic  acid,     , 


5  +2HN02 
NO—  CH 


or  - 


N0  CH 


both  of  which,  on  distillation  with  alkali,  afford  piper  azine. 

Diphenyl-piperazine  (Bischoff,  Ber.  22,  1778).  —  A  mixture 
of  1  88  parts  of  ethylene  dibromide,  93  parts  of  aniline  and 
106  parts  of  powdered  anhydrous  sodium  carbonate  is 
heated  together  with  stirring  at  150°  for  several  hours. 
The  reaction  mixture  is  extracted  with  hot  water,  to  dissolve 
out  sodium  bromide,  steam  is  blown  through  to  remove 
unchanged  materials,  and  the  diphenyl-piperazine  is  filtered 
off,  and  washed.  Yield  90  %. 

Dinitroso-diphenyl-piper  azine  —  Diphenyl-piperazine,  238 
parts,  is  warmed  with  thrice  its  weight  of  22  per  cent. 
hydrochloric  acid,  or  an  equivalent  quantity,  and  the  mixture 
is  then  maintained  at  4°-5°,  with  continual  stirring,  whilst 
an  aqueous  solution  containing  the  equivalent  of  138  parts 
of  100  %  sodium  nitrite  is  slowly  added.  After  the  addition 
is  completed  the  reaction  mixture  is  allowed  to  stand  in  the 
cold  for  several  hours,  when  the  hydrochloride  of  the  dinitroso- 
diphenyl-piperazine  is  filtered  off. 

Piperazine.  —  According  to  the  method  given  in  D.  R.  P. 
60547,  one  Part  by  weight  of  the  dinitroso-diphenyl-piperazine 


250         ORGANIC  MEDICINAL  CHEMICALS 

(hydrochloride)  is  distilled  with  3  parts  of  a  25  % 
solution  of  caustic  soda  until  the  distillate  no  longer  affords 
a  precipitate  with  picric  acid.  Steam  is  blown  through 
towards  the  end  of  the  distillation,  if  necessary.  The  distil- 
late is  neutralised  with  hydrochloric  acid,  concentrated  to 
small  bulk  and  allowed  to  crystallise,  when  piperazine 
dihy drochloride  { (CH2)  2NH }  22HC1 +H2O  is  obtained,  and 
separated.  The  base  is  formed  by  treating  the  hydrochloride 
with  a  concentrated  solution  of  caustic  soda,  and  on  satu- 
rating with  solid  caustic  soda  it  separates  as  an  oil.  This 
is  carefully  removed  and  mixed  with  the  correct  quantity  of 
water  for  the  formation  of  the  hexa-hydrate,  and  on  stirring 
and  cooling  crystallisation  ensues  ;  the  crystals  are  filtered  off 
and  dried,under  diminished  pressure, over  lime  or  caustic  soda. 

According  to  D.  R.  P.  83524,  dinitroso-diphenyl-piperazine 
can  be  split  up  by  boiling  with  strong  mineral  acids,  or  with 
acetic  acid. 

By  another  method,  D.  R.  P.  59222,  sulphur  dioxide  is 
employed,  the  resulting  addition  product  being  resolved, 
by  heating  with  hydrochloric  acid,  into  aminophenol  di- 
sulphonic  acid  and  piperazine  hydrochloride,  thus  : 

NQC6H4N(CH2)4NC6H4NO+4H2S03 

OH 

->    2C6H/NH2       -fHN(CH2)4NH 
N(S03H)2 

Ten  kilos  of  dinitroso-diphenyl-piperazine  are  suspended 
in  300  litres  of  water  and  a  rapid  current  of  sulphur  dioxide 
passed  in  until  all  is  dissolved.  Twenty-two  kilos  of 
hydrochloric  acid  of  23°  Be.  are  then  added  and  the  solution 
concentrated  to  one  half  its  volume.  On  cooling,  part  of 
the  amino-phenol-disulphonic  acid  crystallises  out  in  the 
form  of  needles,  the  remainder,  together  with  piperazine 
hydrochloride,  remaining  in  solution.  After  nitration,  the 
liquid  portion  is  made  alkaline  with  70  kilos  of  33  per  cent, 
caustic  soda,  and  treated  with  superheated  steam  until  the 
distillate  ceases  to  contain  piperazine.  The  distillate  is 
treated  as  before  for  the  isolation  of  the  base. 


DIURETICS  AND    URIC  ACID  SOLVENTS    251 

Instead  of  dinitroso-diphenyl-piperazine,  dinitro-diphenyl- 
piperazine-disulphonic  acid  can  be  employed  for  generating 
piperazine  (D.  R.  P.  63618).  Ten  kilos  of  diphenyl-pipera- 
zine  are  dissolved  in  a  mixture  of  10  kilos  of  concentrated 
sulphuric  acid  and  10  kilos  of  fuming  sulphuric  acid  and 
heated  at  150°  until  a  test  portion  is  completely  soluble  in 
alkali.  The  mixture  is  then  cooled  to  o°  and  nitrated 
with  a  mixture  of  6  kilos  of  88  %  nitric  acid  and  6  kilos  of 
sulphuric  acid  (66°  Be.).  After  nitration  is  complete  the 
mixture  is  run  on  to  600  kilos  of  water  and  ice,  and  the 
solution  neutralised  with  calcium  carbonate.  The  nitrate, 
after  removal  of  calcium  sulphate,  is  boiled  with  6  kilos  of 
sodium  carbonate  cryst.  and,  after  filtering  off  the  calcium 
carbonate,  evaporated  to  dryness.  The  residue  is  added  to 
a  concentrated  solution  containing  10  kilos  of  sodium 
hydrate,  and  the  piperazine  distilled  over. 

Yet  another  alternative  method  of  preparation  starts 
with  an  aryl-sulphon-chloride  or  sulphonamide  and  ethylene- 
diamine  or  ethylene-dibromide  respectively  (D.  R.  P.  70055). 

2C2H4Br2+2RSO2NH2+2NaOH 

->  (RS02N)(CH2)4(NS02R)  ->  (CH2)4(NH)2-f2RH,  etc. 

(CH2NH2)2+2RS02C1 

CH2— NH-SO2R 

->        |  (+C2H4Br2+2NaOH) 

CH2— NH.S02R 
SO2R 

I 
CH2— N— CH2 

-»  I  I         -»     (CH2)4(NH)2-f2RH,  etc. 

CH2— N— CH2 

I 
SO2R 

Dibenzene-disulphon-ethylene-diamide. — A  solution  of  six 
kilos  of  ethylene-diamine  in  25  litres  of  water  is  treated 
alternately  in  small  portions  at  a  time,  with  357  kilos  of 
benzene-sulphon-chloride  and  8  kilos  of  sodium  hydrate 
in  25  litres  of  water,  shaking  or  stirring  being  continuous. 
Dibenzene-disulphon-ethylene-diamide  is  obtained. 


252         ORGANIC  MEDICINAL  CHEMICALS 

Dibenzene-disulphon-piperazide. — Benzene  sulphonaniide 
(33*2  kilos)  and  ethylene  dibromide  (37*6  kilos)  are  dissolved 
in  250  kilos  of  96  %  alcohol,  boiled  and  treated  gradually 
with  40  kilos  of  20  per  cent,  caustic  soda.  Heating 
is  continued  until  the  solution  is  neutral,  when  a  further 
37 '6  kilos  of  ethylene  dibromide  (or  the  corresponding 
quantity  of  ethylene  dichloride)  and  40  kilos  of  20  per  cent, 
caustic  soda  are  added  and  the  mixture  again  boiled  until 
neutral.  After  cooling,  the  dibenzene-disulphon-piperazide 
is  filtered  off,  and  washed  with  (i)  alcohol,  (2)  water, 
(3)  dil.  caustic  soda,  (4)  water. 

The  same  compound  is  obtained  by  treating  the  dibenzene- 
disulphon-ethylene-diamide  obtained  in  the  first  example 
with  ethylene-dihalide  and  caustic  soda  in  alcoholic  solution. 

Hydrolysis  of  Dibenzene-disulphon-piperazide. — This  may 
be  effected  either  by  hydrochloric  or  sulphuric  acid 
(D.  R.  P.  70056)  or  with  chlorsulphonic  acid  (D.  R.  P. 
100232). 

Ten  kilos  of  dibenzene-disulphon-piperazide  are  mixed 
with  50  kilos  of  water  and  50  kilos  of  10-20  %  hydrochloric 
acid  and  heated  in  an  autoclave  at  2OO°-25o°  for  six  hours. 
After  cooling,  the  benzene  is  separated  and,  on  evaporation, 
piperazine  acid  sulphate  is  obtained. 

Or,  one  molecular  equivalent  of  the  piperazide  is  heated 
with  two  equivalents  of  chlorsulphonic  acid  at  130°.  The 
resulting  mass  is  powdered,  after  cooling,  and  introduced 
into  water.  Benzene  sulphonchloride  separates  as  an  oil, 
and  is  removed,  whilst  the  aqueous  solution  is  distilled  with 
alkali,  when  piperazine  is  obtained. 

C6H5S02N(CH2)4NS02C6H5+2S03HC1 

->        2C6H5S02C1+(S03HN)2(CH2)4 

Piperazine  crystallises  with  6  molecules  of  water  in 
colourless  crystals  which  melt  at  44°.  It  absorbs  carbon 
dioxide  with  avidity.  tWhen  anhydrous,  piperazine  fuses 
'  at  104°  and  distils  at  145°. 

It  is  extremely  soluble  in  water,  the  solution  having  a 
strongly  alkaline  reaction.  It  should  give  no  reaction  for 


DIURETICS  AND   URIC  ACID  SOLVENTS    253 

ammonium  salts,  chlorides  or  sulphates,  and  should  sublime 
without  leaving  a  residue. 

Piperazine  is  used  to  prevent  the  formation  of  renal  and 
vesical  calculi,  and  for  the  relief  of  irritation  of  the  bladder 
due  to  excess  of  uric  acid  in  the  urine,  in  cases  of  chronic 
gout,  rheumatism,  etc. 

The  urine  of  patients  to  whom  piperazine  has  been  ad- 
ministered has  been  found  to  contain  more  uric  acid  than  if 
untreated  ;  this  effect  being  more  marked  if  sodium  citrate 
or  sodium  bicarbonate  has  also  been  given. 

ATOPHAN  (2-phenyl-quinoline-4-carboxylic  acid) 

COOH 


249. 


—  -Atophan   was  first  made  by  Doebner  and  Giesecke,  in 
1887  (Ann.  242,  290),  by  the  following  reaction  : 

CHJ 

I 
C6H5NH2  -f  CO—  COOH  -f  CHOC6H6 

93  88  106 

COOH 


249 

Equimolecular  proportions  of  benzaldehyde  and  pyruvic 
acid  (prepared  by  the  distillation  of  tartaric  acid,  alone 
(Ann.  172,  142)  or  (Ber.  14,  321)  with  potassium  bisulphate) 
are  dissolved  in  cold  absolute  alcohol.  A  solution  of  one 
molecular  equivalent  of  aniline,  also  in  absolute  alcohol,  is 
gradually  added.  Heat  is  developed,  and  the  reaction  is 
brought  to  completion  by  boiling  the  mixture,  under  reflux, 
for  3  hours.  On  cooling,  crystals  of  2-phenyl-4-quinoline 
carboxylic  acid  separate  and  are  filtered  ofl,  dissolved  in 


254         ORGANIC  MEDICINAL   CHEMICALS 

sodium  hydroxide  solution,  separated  from  an  insoluble 
impurity,  reprecipitated  with  acid,  and  recrystallised  from 
dilute  alcohol.  Yield  53  %. 

A  variation  of  this  method,  proposed  in  D.  R.  P.  Anmel- 
dung,  20870,  consists  in  gradually  adding  i  molecular 
proportion  of  pyruvic  acid  to  a  boiling  alcoholic  solution  of 
benzylidene  aniline  (i  mol.),  afterwards  refluxing  for  some 
time  and  separating  the  product  as  above. 

An  alternative  process,  in  which  isatin  is  the  starting  out 
material,  was  discovered  by  Pfitzinger  (/.  /.  prakt.  Chim. 
(1897),  56,  292). 

NH/CO  +CH3COC6H5 

147  120 

COOH 

I 
C-CH 

|  +H20 

=C— C6H5 
249 

Isatin,  15  grams,  acetophenone,  22*5  grams,  alcohol, 
122  c.c.,  and  33  %  potassium  hydroxide,  60  c.c.,  are  boiled 
together,  under  a  reflux  condenser  for  6  hours.  The  alcohol 
is  then  distilled  off,  excess  of  acetophenone  is  removed  by 
steam  distillation,  and  the  residue,  after  cooling,  is  extracted 
with  ether  to  remove  impurities.  The  aqueous  solution  is 
freed  from  ether,  cooled,  and  carefully  acidified,  whilst  being 
stirred,  with  dilute  hydrochloric  acid.  After  12  hours  the 
yellow  precipitate  is  filtered  off,  washed  with  water,  and 
dissolved  in  sodium  carbonate.  The  solution  is  diluted  to 
750  c.c.  and,  after  50  grams  of  salt  have  been  dissolved  in 
it,  allowed  to  stand  for  36  hours.  During  this  period  a 
coloured  impurity  is  precipitated.  This  is  filtered  off,  and 
the  atophan  precipitated  by  careful  acidification.  It  is 
finally  purified  by  two  recrystallisations  from  alcohol, 
employing  charcoal  as  a  decolourising  agent.  Yield  65  %. 

A  similar  method  is  given  by  D.  R.  P.  287304. 


DIURETICS  AND    URIC  ACID   SOLVENTS    255 

Fifteen  kilos  of  isatin  are  mixed  with  12  kilos  of  aceto- 
phenone  and  60  kilos  of  33  %  aqueous  caustic  potash  and 
heated  at  9O°-ioo°  for  8  hours,  with  good  stirring.  The 
reaction  mixture  is  then  diluted  with  water  and  filtered. 
The  nitrate  is  carefully  treated  with  acetic  acid  so  long  as  a 
precipitate  of  a  reddish-brown  flocculent  material  is  pro- 
duced. This  is  removed  by  nitration,  and  the  atophan 
precipitated  by  addition  of  the  correct  quantity  of  acetic 
acid.  The  yield  is  stated  to  be  almost  quantitative. 

Atophan  is  a  colourless  crystalline  substance,  melting  at 
209°.  It  is  insoluble  in  cold,  and  nearly  so  in  hot,  water. 
It  is  easily  soluble  in  ether  and  in  hot  alcohol.  It  dissolves 
readily  in  cold  alkalis,  with  formation  of  salts,  and  also,  on 
warming,  in  dilute  acids. 

Atophan  and  its  derivatives  stimulate  the  action  of  the 
kidneys ;  it  slightly  increases  the  flow  of  urine  and  greatly 
increases  the  excretion  of  uric  acid.  It  is  prescribed  in 
acute  gout  and  other  renal  diseases. 

PARATOPHAN,  6-methyl-2-phenyl-4-quinoline-carboxylic 
acid,  and  its  ethyl  ester  (novatophan)  are  recently  introduced 
derivatives  of  atophan  the  value  of  which  is  not  fully  estab- 
lished. 


SECTION  IX.— ORGANO-METALLIC 
COMPOUNDS 

THE  use  in  medicine  of  substances  in  which  atoms  of  the 
metallic  elements  are  directly  linked  to  carbon  atoms  is 
restricted  to  a  very  small  number  of  compounds,  chiefly 
derivatives  of  arsenic.  lonisable  salts  of  antimony,  arsenic, 
bismuth,  iron,  lead,  manganese,  silver  and  zinc  are 
employed  therapeutically  for  various  purposes,  but  prior 
to  the  introduction  of  salvarsan  little  importance  had  been 
attained  by  any  of  the  so-called  organo-metallic  compounds. 
The  discovery  that  sodium  arsanilate  acts  more  powerfully 
as  a  parasiticide  in  the  body  than  in  the  test-tube  led  Ehrlich 
and  his  associates  to  the  most  important  of  modern  discoveries 
in  chemico-therapeutics — salvarsan,  in  which  there  is  a  double 
arsenic  linkage,  the  arsenic  being  in  the  trivalent  form. 
The  danger  and  difficulty  of  administering  organic  arsenic 
compounds  have  been  reduced  by  the  improvements  on 
salvarsan  which  have  already  been  introduced;  further 
progress  in  this  direction  may  still  be  expected. 

Iron  plays  a  definite  and  important  part  in  body  meta- 
bolism, being  essential  to  life,  and  a  constituent  of  haemo- 
globin ;  but  no  readily  available  form  of  its  administration 
has  yet  been  introduced. 

^>-AMINO-PHENYLARSINIC  ACID  (arsanilic  acid) 

NH 

217— 


AsO(OH)2 

This  acid,  the  sodium  salt  of  which  is  employed  in  medicine 
under  the  names  "  Atoxyl  "  and  "  Soamin,"  was  first  prepared 


ORGANO-METALLIC    COMPOUNDS          257 

by  Bechamp  (Bull.  Soc.  Chim.  (1863),  5,  518),  who,  however, 
considered  it  to  possess  the  configuration  \^y  NHAsO  (OH)  2, 
a  supposition  not  corrected  until  1907,  when  Bhrlich  and 
Bertheim  demonstrated  Bechamp  's  compound  to  be  ^-amino- 
phenyl-arsinic  acid. 

Kober  and  Davis  (J.  Amer.  Chem.  Soc.  (1919),  41,  451) 
recommend  the  following  method  of  preparation. 

One  litre  of  76  %  technical  arsenic  acid  is  concen- 
trated to  100  %  by  heating  at  I20°-I4O°  for  12-15  hours, 
then  cooled,  and  stirred  into  1400  c.c.  of  dry,  ice-cold  aniline. 
The  arsenate  so  formed  (aniline  :  acid,  3:2)  is  ground  to  a 
powder,  stirred  at  160°  until  molten,  and  finally  heated  under 
a  reflux  condenser  for  i  to  ij  hours  at  i6o°-i7O°,  and  for 
i  hour  at  i8o°-i85°.  After  cooling  somewhat,  450  c.c. 
of  N/i  sodium  hydroxide  are  added,  the  unchanged  aniline  is 
separated  and  the  aqueous  layer  is  shaken  with  kaolin  or 
kieselguhr,  and  filtered.  The  clear  solution  is  then  treated 
with  100  c.c.  of  6N.  hydrochloric  acid,  and  as  much  more  as 
is  found  to  be  necessary  to  effect  complete  precipitation  of 
th'e  ^-amino-phenyl-arsinic  acid. 

The  almost  solid  mass  is  then  filtered  and  washed  with 
cold  water.  The  sodium  salt  is  prepared  by  neutralising  the 
acid  (i  mol.)  with  sodium  carbonate  (J  mol.)  or  sodium 
hydroxide  (i  mol.)  and  recrystallising  it  from  50  %  aqueous 
alcohol. 

Should  it  be  necessary  to  evaporate  or  boil  aqueous 
solutions  of  sodium  arsanilate,  they  should  be  made  alkaline 
by  the  addition  of  a  second  molecule  of  caustic  soda,  as 
otherwise  considerable  hydrolysis  results  (Ber.  (1914), 

47>  363). 

SODIUM    p  -  AMINO-PHENYL-ARSINATE    ("  Atoxyl  "   or 


'  '  Soamin  ")  C6H4\AsQ(OHj  (ONa)  +5H20,  329,  forms  colour- 

less crystals,  soluble  in  5  parts  of  water,  giving  a  solution 
that  is  neutral  to  litmus.  It  dissolves  in  alcohol,  i  in  125. 
It  contains  22*8  %  of  arsenic.  The  toxicity  of  "  atoxyl  '' 
to  mammals  is  about  one-fortieth  that  of  arsenious  acid. 

i.  17 


258         ORGANIC  MEDICINAL  CHEMICALS 

Aqueous  solutions  become  more  toxic  on  keeping,  due  to 
decomposition. 

"  Atoxyl  "  was  introduced  into  medicine  for  the  treat- 
ment of  trypanosomiasis,  and  it  was  soon  employed  in 
syphilis,  relapsing  fever,  anaemia,  and  skin  diseases.  Cases 
of  blindness,  however,  were  frequently  experienced,  and 
since  the  introduction  of  salvarsan  the  use  of  atoxyl  has  been 
greatly  reduced.  It  is  of  interest  as  being  an  important 
intermediate  in  the  manufacture  of  salvarsan. 

As=As 
ARSENO-PHENYL-GLYCINE  00 

COOHCH2NH    NHCH2COOH 

Arseno-phenyl-glycine,  introduced  by  Ehrlich,  was  the  first 
trivalent  organic  arsenic  compound  introduced.  On  account 
of  its  low  toxicity  and  high  trypanocidal  power  it  constituted 
an  important  advance  on  atoxyl.  It  is  prepared  by  the 
reduction  of  phenyl-glycine  arsanilic  acid. 
Phenyl-glycine-p-amino-phenyl-arsinic  acid 

NH-CH2-COOH 


0 


AsO(OH)2 

Sodium  arsanilate,  27^5  parts,  is  dissolved  in  80  parts  of  hot 
water.  A  solution  of  16  parts  of  mono-chloracetic  acid  in 
20  parts  of  water  is  added  and  the  mixture  boiled  for  6-8 
hours.  On  cooling,  the  phenyl-glycine-arsanilic  acid  crystal- 
lises out  and  is  filtered  off  and  freed  from  any  unchanged 
arsanilic  acid  by  treatment  with  dilute  hydrochloric  acid. 


A  rseno-phenyl-glycine  .  — 
Two  hundred  grams   of  phenyl-glycine    arsanilic  acid   are 


ORGANO-METALLIC  COMPOUNDS          259 

dissolved  in  4  litres  of  hot  water  and  added  to  a  solution 
of  2  kilos  of  sodium  hydrosulphite  in  10  litres  of  water 
containing  600  c.c.  of  loN.  caustic  soda  and  i  kilo  of 
crystallised  magnesium  chloride,  from  which  the  precipi- 
tated magnesia  has  been  removed  by  nitration.  The 
mixture  is  warmed  for  £  hour  on  a  gently  boiling  water 
bath.  The  precipitate  of  arseno-phenyl-glycine  which  has 
separated  is  filtered  off  after  cooling,  washed  with  cold 
water,  and  purified  by  being  dissolved  in  dilute  hot  sodium 
carbonate  solution  and  reprecipitated  with  acetic  acid. 

The  sodium  salt  As2(C6H4NHCH2COONa)2,  named 
"  spirarsyl,"  is  readily  soluble  in  water,  giving  a  neutral 
solution. 

It  has  a  high  trypanocidal  power  combined  with  low 
toxicity,  but  is  inferior  to  salvarsan. 

Salvarsan,  kharsivan,  arsenobillon.  3  .  3'-diamino-4 .  4'- 
dihydroxy-arsenobenzene 

OH  OH 
HONH/N  f/N)NH2HCl'2H20.    475. 


As=As 

— Salvarsan  is  prepared  by  reduction,  generally  with  sodium 
hydrosulphite,  of  3-nitro-4-hydroxy-phenyl-arsinic  acid,  and 
the  various  modifications  of  the  original  method  of  manu- 
facture deal  with  different  means  of  obtaining  the  latter 
substance. 

These  are  :— 

(i)  Nitration  of  ^>-oxy-phenyl-arsinic acid  (D.R.P.  224953), 
which  is  obtained  either  by  heating  phenol  and  arsenic  acid 
(D.R.P.  205616)  or  by  diazotisation  of  ^-amino-phenyl-arsinic 
acid  and  replacement  of  the  diazo-  by  the  hydroxy-  group 
(Trans.  C.  S.  (1908),  93, 1895,  and  Ber.  (1908),  41,1678, 1854). 

OH  OH 

ro2 


AsO(OH)2    AsO(OH)2 


260         ORGANIC  MEDICINAL   CHEMICALS 

(2)  By  nitration  of  oxalyl-amino-phenyl-arsinic  acid,  and 
boiling  the  product  with  alkali,  when  the  NJTCO'COOH 
group  is  replaced  by  OH(D.R.P.  31969),  with  the  elimina- 
tion of  oxalic  acid  and  ammonia. 

NH-CO'COOH        NH'COCOOH         OH 


2  /NN02 


AsO(OH)2  AsO(OH)2  AsO(OH)2 

(3)  By  nitration  of  ^>-chlorophenyl-  arsinic  acid,  prepared 
by  treating  diazotised  para-chloraniline  with  sodium  arsenite 
(Bart's  reaction,  D.R.PP.  250264,  254345),   after  which  by 
digestion  with  alkali  the  Cl  atom  is  replaced  by  OH. 

Cl  Cl  Cl  OH 

X\N02 

\x  \/ 

N=NC1  AsO(OH)2         AsO(OH)2  AsO(OH)2 

D.R.P.  245536). 

(4)  Ortho-nitrophenol    is    coupled  with  diazotised  sul- 
phanilic  acid  and  the  resulting  azo-compound 

OH  S03H 

N°00       •;         ..: 

N=N 

is  reduced  to  i-amino-3-nitro-4-hydroxy-benzene,  into  which 
the  arsinic  acid  radicle  is  introduced,  by  Bart's  reaction,  in 
place  of  the  amino  group  (D.R.P.  258059).  This  process  is  un- 
satisfactory, however,  as  in  the  case  of  w^a-nitroamines  the 
reaction  between  the  diazo  compound  and  sodium  arsenite 
gives  rise  only  to  very  small  yields  of  the  required  arsinic 
acid  (Jacobs,  Heidelberger,  and  Rolf,  /.  Am.  Chem.  Soc. 
(1918),  40,  1580). 

(5)  From  />-dimethylamino-phenyl-arsinic  acid. 

The  specific  reducing  agent  by  which  nitro-hydroxy- 
phenyl-  arsinic  acid  is  converted  into  salvarsan  is,  as  stated 
above,  sodium  hydrosulphite.  According  to  D.R.P.  271894 


ORGANO-METALLIC   COMPOUNDS          261 

the  operation  is  successfully  effected  by  hypophosphorous 
and  hydriodic  acids,  employed  together. 

(i)  Preparation  of  Para-hydroxyphenyl-arsinic  acid 

OH 


0 


AsO(OH)2 

Phenol,  94  parts,  and  crystallised  arsenic  acid,  151  parts, 
are  mixed  and  heated  together  with  stirring  for  4  hours  at 
150°.  The  resulting  mass  is  extracted  with  1000  parts  of 
hot  water,  and  the  filtered  solution  evaporated  as  far 
as  possible  under  diminished  pressure.  The  residue  is 
repeatedly  extracted  with  acetone.  After  removal  of  the 
solvent  the  crude  arsinic  acid  is  obtained  as  an  oil  which 
gradually  solidifies.  Conant  (/.  Amer.  Chem.  Soc.  (1919), 
41,  431)  employs  a  10  %  excess  of  arsenic  acid  and  heats  at 
I47°-I57°  for  3  hours.  The  aqueous  solution  of  the  crude 
acid  is  filtered  from  tar,  treated  with  barium  hydroxide 
until  the  brown  colour  begins  to  change  to  pink,  and  then 
extracted  with  ether  to  remove  tarry  matter.  More  baryta 
is  then  added  until  a  test  portion,  after  rendering  it  alkaline 
and  filtering,  shows  the  presence  of  barium  ions.  The  solu- 
tion is  then  made  just  alkaline  with  sodium  hydroxide  and 
filtered.  The  barium  is  removed  by  treatment  with  sodium 
sulphate  and  the  filtrate  evaporated  to  a  syrup.  Sulphuric 
acid  is  added  until  the  red  colour  changes  to  yellow,  and  the 
impurities  which  separate  are  filtered  off.  The  filtrate  is 
neutralised  with  soda  and  evaporated  to  dryness,  when  a 
mixture  of  sodium  sulphate  and  sodium  ^-hydroxyphenyl- 
arsinate  is  obtained.  This  can  be  nitrated  directly,  or  the 
latter  compound  may  be  extracted  with  boiling  alcohol  and 
crystallised.  Yield  21*5  %. 

Alternatively,  the  syrupy  residue  containing  the^>-hydroxy- 
phenyl  arsinic  acid  can  be  treated  as  follows  (E.P.  6322/1915). 
Eighty  parts  are  dissolved  in  80  parts  of  warm  water  and  the 
solution  neutralised,  after  cooling,  with  a  solution  of  16  parts 


262         ORGANIC  MEDICINAL  CHEMICALS 

of  caustic  soda  in  80  parts  of  water.  After  filtration  from  some 
separated  impurities  the  filtrate  is  concentrated  and  allowed 
to  crystallise.  Sixty  parts  of  crude  sodium  ^-hydroxy- 
phenyl  arsinate  are  obtained.  It  may  be  purified  by 
dissolving  in  120  c.c.  of  boiling  water,  and  adding  250  parts 
of  absolute  alcohol.  After  cooling,  30  parts  of  pure  sodium 
^>-hydroxyphenyl-arsinate  crystallise  out,  a  further  5  parts 
being  obtained  by  concentration  of  the  mother  liquors. 

By  another  method  (see  Trans.  C.  S.  (1908),  93,  1895) 
329  parts  of  sodium  para-amino-phenyl-arsinate  (-j-5H2O) 
are  dissolved  in  1000  parts  of  water  containing  300  parts 
of  loN.  hydrochloric  acid  and  diazotised,  at  o°-5°,  with 
sodium  nitrite,  69  parts  (100  %)  dissolved  in  100  parts  of 
water.  After  standing  for  an  hour  the  solution  is  gradually 
heated  up  to  100°,  and  then,  when  evolution  of  nitrogen  has 
ceased,  partially  neutralised  with  100  c.c.  of  loN.  sodium 
hydroxide,  but  left  still  just  acid  to  congo  red,  and  evaporated, 
under  reduced  pressure,  to  dryness.  The  residue  is  powdered, 
re-dried  if  necessary,  and  extracted  with  boiling  acetone. 
The  solvent  is  partially  removed  from  the  extract  and, 
after  cooling,  ^>-hydroxyphenyl-arsinic  acid  crystallises  out. 
M.p.  i73°-i74°. 

It  may  be  purified  by  recrystallisation  from  glacial  acetic 
acid.  It  is  readily  soluble  in  water  and  alcohol. 

Nitration  of  p-hydroxyphenyl-arsinic    acid  to   ^-nitro-^- 

OH 
hydroxyphenyl-arsinic  aaW(|NO2  (D.R.P.  224953). — Sodium 


AsO(OH)2 

para-oxyphenyl-arsinate,  dried  at  80°,  144  parts,  is  added, 
in  small  portions  at  a  time,  to  450  parts  by  vol.  of  con- 
centrated sulphuric  acid,  which  is  kept  at  o°.  A  mixture 
of  39  parts  by  vol.  of  nitric  acid  (sp.  gr.  1*4)  and  39 
parts  by  vol.  of  concentrated  sulphuric  acid  is  then  added, 
at  the  same  temperature,  with  constant  stirring.  When 
addition  of  the  nitrating  acid  is  complete,  the  mixture  is 
allowed  to  stand  for  some  time  and  the  temperature  to  rise 
to  10°.  It  is  then  poured  on  to  2250  grams  of  ice,  and  after 


ORGANO-METALLIC  COMPOUNDS          263 

12  hours'  standing  in  the  cold  the  precipitated  3-nitro-4~ 
hydroxyphenyl-arsinic  acid  is  filtered  off. 

NH-COCOOH 

(2)  Oxanil-4-arsinic  acid  f  J     Sodium   />-aminophenyl- 

AsO(OH)2 

arsinate  (-f5H2O),  347  parts,  is  mixed  thoroughly  with 
378  parts  of  crystallised  oxalic  acid.  The  mixture  is 
heated,  with  constant  stirring,  at  I2O°-I30°,  until  the  bulk 
of  the  water  has  been  removed  and  the  mass,  which  at 
first  melted,  has  resolidified.  The  temperature  is  then 
raised  slowly  to  160°  and  heating  continued  until  the  mass 
is  again  solid  and  in  powder  form.  After  cooling  it  is 
treated  with  3000  parts  of  water,  390  vols.  of  hydrochloric  acid 
(sp.  gr.  1*12)  are  added,  and  the  mixture  is  stirred  for  half 
an  hour.  The  solid  oxanil-4-arsinic  acid  is  then  filtered  off, 
purified  by  recrystallisation  from  water,  and  thoroughly 
dried.  Alternatively  it  may  be  purified  by  dissolving  in 
normal  caustic  soda  solution  and  reprecipitation,  after  being 
filtered,  with  hydrochloric  acid. 

NH-COCOOH 
l-nitw-4-arsinic   acid   QN°2        and  l-nitw-4-amino- 

AsO(OH)2 

phenyl-arsinic  acid. — The  dried  oxanil-arsinic  acid,  115*6 
parts,  is  dissolved  in  300  vols.  of  concentrated  sulphuric  acid 
at  o°-5°.  A  mixture  of  26  vols.  of  nitric  acid  (sp.  gr.  1-4)  and 
26  vols.  of  sulphuric  acid  is  added,  with  stirring,  the  tempera- 
ture being  kept  at  or  below  5°.  The  mixture  is  allowed  to 
stand  for  some  time  after  the  addition  is  completed  and 
is  then  poured  into  1500  parts  of  cold  water,  when  the 
nitro-oxanil-arsinic  acid  separates  as  a  crystalline  paste. 
The  whole  is  heated  to  boiling,  a  clear  yellow  solution 
being  obtained.  Boiling  is  continued  until  the  acidity 
increases  no  further,  and  the  mixture  is  cooled,  when  3- 
nitro-4-amino-phenyl-arsinic  acid  crystallises  out  in  sulphur- 
coloured  needles,  which  are  only  sparingly  soluble  in  cold 
water.  It  is  filtered  off  and  washed  with  cold  water. 


264         ORGANIC  MEDICINAL  CHEMICALS 

Ten  kilos  are  dissolved  (D.  R.  P.  235141)  in  60  litres  of 
caustic  potash  (36°  Be.)  and  the  solution  heated  at  80°, 
until  a  portion  is  shown  by  test  to  be  free  from  substances 
containing  an  amino  group.  After  cooling,  the  solution  is 
made  acid  to  congo  red,  with  hydrochloric  acid,  when 
3-nitro-4-hydroxyphenyl-arsinic  acid  is  precipitated. 

Alternatively  the  3-nitro-4-oxanil-arsinic  acid  is  separated 
by  filtration  and  heated,  as  above,  with  caustic  alkali 
solution. 

By  another  protected  process  (D.R.  P.  232879)  the  urethane 
of  ^>-amino-phenyl-arsinic  acid,  prepared  by  condensing  the 
acid  with  ethyl-chloro-carbonate,  is  nitrated  and  treated  as 
is  the  oxalyl  compound. 

Cl 

(3)  4-Chlorophenyl-arsinic  acid  f  J   This  compound  is 

AsO(OH)2 

prepared  from  para-chloraniline  by  Bart's  reaction  (D.  R.  P. 
250264). 


Para-chloraniline,  074  part,  is  dissolved  in  10  parts  of  water 
and  2  parts  of  hydrochloric  acid  (sp.  gr.  1*16),  and  diazotised 
at  10°  with  the  required  amount  of  sodium  nitrite.  The 
diazo  solution  is  then  mixed  with  2  parts  of  sodium  arsenite 
dissolved  in  5  parts  of  water.  The  mixture  is  made  alkaline 
and  gently  heated.  When  the  evolution  of  nitrogen  has 
ceased,  the  reaction  mixture  is  filtered  from  tarry  impurity 
and  the  para-chlorophenyl-arsinic  acid  precipitated  by  the 
addition  of  hydrochloric  acid.  According  to  the  British 
specification  (E.  P.  568/1911),  3  parts  of  sodium  arsenite 
dissolved  in  5  parts  of  water  and  i  part  of  96  %  alcohol  are 
employed,  and  the  mixture  heated  to  70°. 

In   a  subsequent  patent   (D.    R.    P.   268172)  copper  is 
employed  as  a  catalyst,  50  parts  of  copper  paste  being  added 


ORGANO-METALLIC   COMPOUNDS  265 

to  a  solution  of  51  parts  of  sodium  arsenite  in  150  parts  of 
water  and  60  parts  of  40  %  caustic  soda.  D.  R.  P.  264924, 
dealing  with  the  preparation  of  phenyl-arsinic  acid  from  aniline 
by  the  Bart  method,  utilises,  as  the  catalyst,  freshly  prepared 
cuprous  oxide,  precipitated  from  alkalised  copper  nitrate 
by  glucose.  Cobalt,  nickel,  and  silver  and  their  salts  have 
been  proposed  as  catalysts,  as  well  as  copper. 

Jacobs,  Heidelberger  and  Rolf  (/.  Am.  Chem.  Soc.  (1918), 
40,  1580),  in  carrying  out  the  Bart  reaction,  convert  the 
diazo-compounds  into  the  iso-diazo  salts  by  pouring  into  an 
excess  of  caustic  soda  at  o°.  The  arsenite  is  then  added 
and  the  reaction  mixture  heated  at  6o°~70°  until  the  evolution 
of  nitrogen  has  ceased. 

(4)  From  dimethyl-amino-phenyl-arsinic  acid 

N(CH3)2 


0 


AsO(OH)2 

• 

(D.  R.  P.  200065). — A  mixture  of  15  parts  of  dimethyl 
aniline  and  25  parts  of  arsenious  chloride  is  heated  at 
100°  for  2  hours,  and  is  then  poured  in  300-400  parts 
of  cold  water.  Excess  of  aqueous  caustic  soda  is  added 
until  the  ^-dimethyl-aniino-phenyl  arsenious  oxide  is  dis- 
solved. After  removing  unchanged  dimethylaniline  by  ex- 
traction with  light  petroleum,  an  excess  of  30  %  hydrogen 
peroxide  is  added  and  ^-dimethyl-amino-phenyl-arsinic  acid 
precipitated  with  acetic  acid. 
.  4-dimethyl-amino-3-nitro-phenyl-arsinic  acid 

N(CH3)2 

ro2 


AsO(OH)2 

(F.  P.  449373). — One  hundred  parts  of  dry  dimethyl- 
amino-phenyl-arsinic  acid  are  dissolved  at  below  15° 
in  250  parts  of  concentrated  sulphuric  acid  and  nitrated 
with  a  mixture  of  35  parts  of  nitric  acid  (sp.  gr.  i'49) 


266         ORGANIC  MEDICINAL   CHEMICALS 

and  150  parts  of  sulphuric  acid,  the  temperature  being  kept 
below  15°.  After  standing  for  some  time  the  reaction 
mixture  is  poured  on  to  ice,  the  yellow  precipitate  filtered 
off,  washed,  dissolved  in  aqueous  sodium  carbonate  solution 
and  reprecipitated,  after  filtration,  by  very  dilute  mineral 
acid.  It  may  be  further  purified  by  crystallisation  from  hot 
water. 

Conversion  of  dimethyl-amino-nitro-phenyl-arsinic  acid  to 
S-nitro-^-hydroxyphenyl-arsinic  acid  (Fr.  Pat.  451078). — 
Five  hundred  parts  of  the  nitro-acid  are  dissolved  in  a 
solution  of  500  parts  of  caustic  potash  in  1500  parts  of  water 
and  the  mixture  maintained  at  8o°-9O°  until  it  becomes 
nearly  solid.  Ice-cold  water  (2000  parts)  and  concentrated 
hydrochloric  acid  are  added  successively,  the  precipitate 
is  dissolved  in  hot  water,  and  the  filtered  solution  treated 
with  sodium  acetate  (i  mol.)  and  animal  charcoal.  It  is 
filtered  again  and  acidified  with  hydrochloric  acid,  when 
3-nitro-4-oxyphenyl-arsinic  acid  separates  either  in  yellow, 
rhombohedral  plates,  or  in  tufts  of  almost  colourless  needles. 
Reduction  of  Nitro-hydroxyphenyl-arsinic  acid  to  Sal- 
OHOH 

varsan          2f  J  f  J^-"-2. — The  preparation  of  salvarsan  by 

As=As 

the  reduction  of  3-nitro-4-hydroxyphenyl-arsinic  acid  with 
sodium  hydrosulphite  in  one  operation  is  thus  described  by 
Kober  (J.  Amer.  Chem.  Soc.  (1919),  41,  442). 

Magnesium  chloride,  220  grams,  is  dissolved  in  5500  cc.  of 
distilled  water,  and  sodium  hydrosulphite,  noo  grams,  quickly 
added,  with  stirring.  To  this  solution  are  then  added, 
with  stirring,  85  grams  of  crude  3-nitro-4-hydroxyphenyl- 
arsinic  acid  dissolved  in  290  c.c.  of  2N.  sodium  hydroxide 
and  diluted  with  1700  c.c.  of  water.  The  mixture  is  allowed 
to  stand  at  room  temperature,  or  it  is  slowly  warmed  in  a 
water  bath  at  40°,  until  the  suspension,  which  consists 
mostly  of  impurities,  besides  a  little  of  the  salvarsan  base, 
has  separated.  The  mixture  is  then  rapidly  filtered  through 
hard  paper,  or  alundum  ware.  The  weight  of  the  residue 


ORGANO-METALLIC   COMPOUNDS          267 

rarely  exceeds  3  to  4  grams,  or  4  to  5  per  cent,  of  the  total 
yield. 

The  clear  yellow  filtrate  is  then  digested  at  5o°-6o°  for 
2  to  2  J  hours,  during  which  time  the  salvarsan  base,  3.3'- 
diamino-4 . 4'-dihydroxy-arsenobenzene,  separates  out  as  a 
yellow  precipitate. 

The  above  differs  from  Bhrlich  and  Bertheim's  method 
(Ber.  (1912),  45,  756)  only  in  respect  of  the  nitration,  which 
these  workers  omitted.  The  precipitate  is  filtered  off, 
washed  with  water  at  o°,  and  pressed.  By  Ehrlich  and 
Bertheim's  process  it  is  dissolved  in  anhydrous  methyl 
alcohol,  725  c.c.  for  the  above  quantities,  and  treated  with 
0*75  mol.  of  hydrogen  chloride  dissolved  in  methyl  alcohol. 
Ether  is  added  to  the  filtered  solution,  whereby  salvarsan 
hydrochloride  is  precipitated.  It  is  filtered  off  quickly, 
washed  with  ether,  and  dried  in  an  inert  atmosphere,  such 
as  CO2,  or  in  vacua,  at  65°.  Yield  (E.  &  B.)  82  %. 

Kober,  loc.  cit.,  considers  that  the  very  variable  toxicity 
of  salvarsan,  of  which  50  per  cent,  of  that  manufactured  in 
America  fails  to  pass  the  prescribed  physiological  tests, 
may  be  attributable  to  impurities  concomitant  with  this 
methyl  alcohol-ether  treatment.  He  suspends  washed 
base  in  400  c.c.  of  distilled  water  at  o°  and  dissolves  it 
by  addition  of  150  c.c.  of  2N.  caustic  soda.  The  alkaline 
solution  is  filtered  through  an  alundum  anaerobic  filter, 
and  150  c.c.  of  i  :  i  hydrochloric  acid  at  o°  are  added  to 
the  clear  filtrate.  This  precipitates  the  base  and  redissolves 
it  as  the  dihydrochloride.  The  solution  is  diluted  with 
distilled  water  at  o°  to  bring  the  total  volume  to  1700  c.c. 
It  is  then  allowed  to  flow,  slowly  and  with  stirring,  into  a 
mixture,  cooled  to  o°,  of  1625  c.c.  of  pure  concentrated 
hydrochloric  acid  and  1625  c.c.  of  water.  Salvarsan  di- 
hydrochloride is  precipitated  as  a  greyish-white  precipitate. 
It  is  filtered,  and  dried  in  vacuo  at  a  low  pressure,  in  presence 
of  calcium  chloride  and  solid  caustic  soda.  After  12  hours 
or  more,  hydrogen  is  introduced,  to  equalise  the  pressure, 
and  the  salvarsan  is  ground  and  further  dried  until  of  con- 
stant weight.  Yield  75  %. 


268         ORGANIC  MEDICINAL   CHEMICALS 

From  Fargher  and  Pyman's  work  (Trans.  C.  S.  (1920), 
117,  372),  Kober's  purification  is  of  doubtful  value.  Com- 
mercial salvarsan  contains  i  to  3  per  cent,  of  sulphur,  which 
occurs,  at  least  in  part,  in  the  form  of  a  sulphamo-group 
NH — SO3H.  When  obtained  free  from  sulphur  salvarsan  is 
less  readily  soluble  and  therefore  less  suited  for  clinical  use. 

The  following  method  of  reduction  has  also  been  employed 
(D. R.P.  271894) .  Twenty  parts  of  3-nitro-4-hydroxyphenyl- 
arsinic  acid  are  mixed  with  100  vols.  of  25  %  hypophosphorous 
acid  solution  and  70  vols.  of  glacial  acetic  acid,  and  the 
mixture  heated  on  the  water  bath  with  stirring  and  in 
absence  of  air.  Dinitro-dihydroxy-arseno-benzol  separates 
out  as  a  yellow  crystalline  precipitate.  After  about  an  hour's 
heating  12  parts  of  potassium  iodide  are  added.  A  vigorous 
reaction  takes  place,  and  the  precipitate  passes  into  solution, 
which  acquires  a  faint  yellow  colour.  After  cooling  it  is 
poured  into  150  vols.  of  concentrated  hydrochloric  acid,  and 
the  mixture  is  saturated  with  HC1  gas.  The  dihydrochloride 
of  salvarsan  separates  out  and  is  filtered  off,  washed  succes- 
sively with  concentrated  hydrochloric  acid,  alcoholic  hydro- 
chloric acid  and  ether,  and  dried  in  vacuo. 

By  a  variation  of  the  procedure  the  reduction  solution  is 
poured  into  600  vols.  of  alcohol,  when  the  hypophosphite 
of  the  base  is  precipitated  as  a  yellowish-white  powder. 
This  is  converted  into  hydrochloride,  base,  or  sodium  salt,  as 
desired.  Prepared  in  this  manner  salvarsan  is  less  soluble  in 
water  or  methyl-acohol  than  when  reduced  by  the  previously 
described  method. 

Electrolytic  Reduction  of  3-nitro-4-hydroxyphenyl- 
arsinic  acid.  (D.  R.  P.  270568.) — Fifty  parts  of  3-nitro- 
4-oxyphenyl-arsinic  acid  are  dissolved  in  150  parts  of  water 
and  12*5  parts  (i  mol.)  of  potassium  carbonate.  This  is 
placed  in  the  cathode  chamber  of  an  electrolytic  cell,  the 
anode  chamber  containing  a  10  to  20  %  solution  of  potassium 
carbonate.  L,ead  electrodes  are  employed,  and  the  cathode 
liquor  is  well  stirred.  A  current  of  10  to  25  amps,  per  100 
sq.  cm.  is  employed,  and  it  is  recommended  that  a  stream 
of  CO2  be  passed  through  the  liquor  during  electrolysis. 


ORGANO-METALLIC   COMPOUNDS          269 

The  current  is  passed  until  the  solution  is,  as  far  as  it  can  be, 
decolourised.  The  resulting  salvarsan  is  precipitated,  with 
sulphuric  acid,  as  the  sulphate.  It  is  claimed  that  the 
product  afforded  by  this  electrolytic  method  of  reduction 
possesses  a  lower  degree  of  toxicity. 

If  electrolysed  in  an  acid  solution  3  .  3'-dinitro-4 . 
4'- dihydroxy  -  arseno  -  benzene  is  produced.  This  may  be 
reduced  further,  to  salvarsan,  by  electrolysis  in  an  alkaline 
solution. 

The  reduction  of  3-nitro-4-hydroxyphenyl-arsinic  acid  can 
also  be  effected  in  stages.  By  employing  sodium  amalgam,  or 
ferrous  sulphate  and  caustic  soda,  s-amino-^-hydroxyphenyl- 
arsinic  acid  is  obtained.  This  is  reduced  further,  by  the  action 
of  sulphurous  acid  in  the  presence  of  hydriodic  acid,  to 
3-amino-^-hydroxyphenyl-arseniom  oxide,  which  is  converted 
into  salvarsan  by  reduction  with  hypophosphorous  acid  used 
in  conjunction  with  hydriodic  acid.  No  advantage  can  be 
claimed  for  this  mode  of  procedure.  Another  direct  method 
of  reduction  depends  upon  the  formation  of  hydrosulphurous 
acid  in  situ.  %  (B.  P.  21421/1914.) 

One  hundred  grams  of  3-nitro-4~hydroxyphenyl-arsinic 
acid  are  dissolved  in  500  c.c.  of  water  containing  a  sufficient 
quantity  of  soda  to  produce  a  neutral  solution,  50  grams  of 
zinc  chloride  or  acetate  are  then  added,  followed  successively 
by  a  concentrated  aqueous  solution  of  100  grams  of  sodium 
sulphite,  glacial  acetic  acid,  150  c.c.,  and  zinc  dust,  200  grams, 
the  emulsion  being  thoroughly  stirred.  Five  hundred  c.c. 
of  hydrochloric  acid  (18  %)  are  then  added  very  slowly, 
the  temperature  being  between  25°  and  35°.  The  resulting 
clear  solution  is  warmed  to  50°  and  treated  gradually  with 
a  further  570  c.c.  of  18  %  hydrochloric  acid.  After  20-30 
minutes  the  solution  is  filtered  rapidly  and  the  filtrate 
treated  with  magnesium  sulphate,  when  salvarsan  sulphate 
is  precipitated.  It  is  claimed  that  the  presence  of  sulphurous 
acid  prevents  the  reduction  going  beyond  the  arsenobenzene 
stage  to  primary  arsine. 

Salvarsan,  which  is  the  dihydrochloride  of  diamino-dihy- 
droxy-arseno-benzene,  is  a  pale  yellow  powder,  soluble  in  5 


270         ORGANIC  MEDICINAL  CHEMICALS 

parts  of  water.  Its  solution  has  a  strongly  acid  reaction.  The 
solubility  is  increased  by  certain  impurities  which  accompany 
it.  It  is  moderately  soluble  in  methyl,  sparingly  soluble  in 
ethyl  alcohol,  and  almost  insoluble  in  acetone,  ether,  or 
glacial  acetic  acid.  On  account  of  the  readiness  with  which 
salvarsan  undergoes  change  in  air,  with  formation  of  highly 
toxic  impurities,  it  is  preserved  in  sealed  tubes  in  an  atmo- 
sphere of  an  inert  gas. 

When  heated,  salvarsan  hydrochloride  does  not  melt ; 
it  darkens  at  160°  and  begins  to  char  about  ,180°. 

When  perfectly  pure  the  dihydrochloride  is  practically 
colourless.  The  appearance,  however,  is  no  criterion  of 
physiological  purity,  as  very  light-coloured  preparations  have 
been  found  on  occasion  to  be  extremely  toxic.  Theoretically 
salvarsan  dihydrochloride,  if  anhydrous,  should  contain 
34-2  %  of  arsenic  ;  if  it  contains  2H2O,  31-6  %. 

Ewins  (Trans.  C.  S.  (1916),  109,  1355)  found  from  30-4  % 
to  31  *45  %  of  arsenic  in  four  commercial  samples  examined. 
Kober  (loc.  cit.)  considers  that  no  justification  exists  for 
assuming  the  commercial  product  to  contain  two  molecules  of 
water,  and  that,  as  made  by  the  patented  method,  it  contains 
instead  one  molecule  of  methyl  alcohol.  Samples  prepared 
by  Kober's  method  (see  above)  appear  to  have  contained 
from  one  to  rather  more  than  two  molecules  of  water,  and 
afforded  from  30-3  %  to  32*89  %  of  arsenic.  But  Fargher 
and  Pyman  found  that  salvarsan  if  precipitated  trom  methylic 
alcohol  solution  with  ether  contains  no  combined  organic 
solvent,  though  if  precipitated  with  acetone  from  methyl- 
alcohol  it  contains  one  molecule  of  acetone. 

All  batches  of  salvarsan,  neo-salvarsan,  etc.,  made  in  this 
country  and  in  the  United  States  are  required  to  satisfy 
physiological  tests  of  freedom  from  toxicity,  carried  out  by 
a  public  authority,  before  they  are  allowed  to  be  issued. 

Salvarsan,  neo-salvarsan,  galyl,  and  luargol,  are  the  most 
powerful  drugs  so  far  available  for  combating  syphilis.  They 
are  specific  for  primary  and  secondary  syphilis,  and  in  many 
cases  have  been  used  with  success  even  in  hereditary 
syphilis  and  in  tertiary  para-syphilitic  conditions. 


ORGANO-METALLIC    COMPOUNDS          271 

Not  only  syphilis  but  other  diseases  attributable  to 
spirillosa,  such  as  yaws,  frambcesia,  and  (probably)  perni- 
cious anaemia  are  beneficially  treated  by  arsenic  administered 
in  the  arsenobenzol  form. 

Salvarsan  is  administered  by  intravenous  or  intramus- 
cular injection,  a  solution  being  employed  which  is  pre- 
pared by  treating  the  salt  with  sufficient  caustic  soda 
to  precipitate  the  base  and  redissolve  it  as  the  di-sodium 
salt. 

To  avoid  the  inconvenience  of  this  procedure  the  sodium 
salt  of  salvarsan  was  prepared  and  is  marketed  in  the  form 
of  a  yellowish  powder,  which  is  readily  soluble  in  water. 

Sodium  Salvarsan  (E.  P.  15931/1912). — Six  grams  of 
salvarsan  dihydrochloride  are  mixed  with  60  c.c.  of  strongly 
cooled  methyl  alcohol  and  the  mixture  treated  with  5-05  c.c. 
of  loN.  caustic  soda  solution,  with  stirring.  To  the  solution 
are  added  i'2  gram  of  sodium  formaldehyde-sulphoxylate 
dissolved  in  3  c.c.  of  water,  and  the  mixture  is  then  poured 
into  a  mixture  of  300  c.c.  of  methyl  alcohol  and  240  c.c.  of 
pure  ether.  The  sodium  salt  is  precipitated,  and  is  filtered 
off,  washed  with  ether,  and  dried  in  vacuo  over  sulphuric 
acid.  All  these  operations  are  carried  out  in  absence  of  air. 

NEO-SALVARSAN  (sodium  3  :  3'-diamino-4  :  4'-dihydroxy- 
arseno-benzene-N-methylene-sulphinate) 

OH    OH 
NH^  ANH-CH20'SONa 

As=As 

The  inconvenience  involved  in  the  preparation  of  sal- 
varsan solution  for  injection  led  Khrlich  to  search  for  a 
soluble  neutral  derivative  which  would  not  possess  the 
same  disadvantages.  The  methylene-sulphinate,  prepared 
by  treating  the  salvarsan  base  with  sodium  formaldehyde 
sulphoxylate,  proved  the  most  satisfactory  of  the  substances 
made  and  tested,  and  was  named  Neo-salvarsan. 

Twenty-five  parts  of  salvarsan  dihydrochloride  are 
dissolved  in  250  parts  of  water  and  mixed  at  room 


272         ORGANIC  MEDICINAL   CHEMICALS 

temperature  with  a  solution  of  25  parts  of  sodium  formal- 
dehyde-sulphoxylate  in  250  parts  of  water.  After  one 
hour  80  parts  of  a  10  %  solution  of  sodium  carbonate  are 
added,  when  a  clear  solution  is  formed.  Addition  of  100 
parts  by  vol.  of  12  %  hydrochloric  acid  then  precipitates 
the  meth34ene-sulphinic  acid  derivative  of  salvarsan,  con- 
taining one  CH2SO2H  group.  In  order  to  make  neo- 
salvarsan — the  sodium  salt  of  the  acid  thus  obtained — 20 
parts  of  the  acid  are  suspended  in  70-  80  parts  of  water,  and 
brought  into  solution  with  the  aid  of  20  parts  of  twice 
normal  sodium  hydroxide.  The  solution  is  then  allowed  to 
flow,  with  stirring,  in  a  thin  stream  into  1000  parts  by  vol. 
of  alcohol.  The  sodium  salt  is  precipitated,  and  is  filtered 
oft,  washed  with  cold  water,  and  dried  in  vacuo.  (D.  R.  P. 

24576.) 

Acetone  also  may  be  used  as  a  precipitant,  or  the  aqueous 
solution  of  the  sodium  salt  may  be  evaporated  to  dryness 
under  diminished  pressure.  According  to  D.  R.  P.  260235 
neo-salvarsan  having  a  lower  toxicity  can  be  prepared  by 
operating  in  alcohol  solution.  Methyl  and  ethyl  alcohol, 
glycol,  and  glycerol  are  cited. 

Thirty-one  parts  of  sodium  formaldehyde-sulphoxylate 
dissolved  in  50  parts  of  water  are  added  to  a  solution  of 
50  parts  of  salvarsan  base  in  200  parts  of  ethylene-glycol. 
After  five  minutes  the  solution  is  neutralised  with  sodium 
carbonate,  and  allowed  to  flow  into  a  large  quantity  of  alcohol, 
alcohol  and  ether,  or  acetone,  when  neo-salvarsan  is  precipi- 
tated.    Neo-salvarsan  can  also  be  prepared  directly  from 
3-nitro-4-hydroxyphenyl-arsinic  acid.    One  part  of  this  is  dis- 
solved in  5  parts  of  water  and  3*8  parts  of  4  %  caustic  soda, 
and  warmed  with  2  parts  of  sodium-formaldehyde-sulphoxy- 
late  dissolved  in  10  parts  of  water,  when  a  yellow  precipitate  of 
the  free  sulphinic  acid  is  gradually  formed  (D.  R.  P.  260235). 
When  this  no  longer  continues  to  increase  in  amount,  it  is 
filtered  off,  washed  with  water,  and  converted  into  the  sodium 
salt  in  the  way  described  above.     By  another  variation,  10 
parts  of  3-amino-4-hydroxyphenyl-arsinic  acid  are  dissolved  in 
100  parts  of  water  containing  2*3  parts  of  sodium  carbonate 


ORGANO-METALLIC   COMPOUNDS          273 

and  the  solution  mixed  with  one  of  20  parts  of  sodium 
formaldehyde-sulphoxylate  in  100  parts  of  water.  Normal 
hydrochloric  acid,  41  parts,  is  then  added,  and  the  mixture 
digested  for  several  hours  at  4O°-6o°.  After  cooling,  the 
sulphoxylic  acid  is  precipitated  by  acidification  with  dilute 
sulphuric  acid. 

Neo-salvarsan  is  a  pale  yellow  powder  which  is  readily 
soluble  in  water,  affording  a  neutral  solution.  It  contains 
usually  about  20  %  of  arsenic.  It  is  used  for  the  same 
purposes  as  salvarsan,  having  a  very  similar  physiological 
action.  It  is  becoming  the  more  extensively  used  drug  on 
account  of  its  greater  solubility  and  the  consequent  greater 
ease  with  which  the  solution  for  injection  may  be  prepared. 

Co-ordination  Compounds  of  Salvarsan  and  Neo- 
salvarsan. — Compounds  of  salvarsan  with  copper,  silver, 
gold,  platinum,  mercury,  palladium,  iridium,  ruthenium, 
and  osmium,  in  which  the  arsenobenzene  enters  into  com- 
bination with  one  or  two  molecular  proportions  of  the  metallic 
salt  in  such  a  way  that  the  metal  is  held  in  a  non-ionisable 
condition,  were  discovered  by  Ehrlich  and  Karrer  (Ber. 
(1915),  48,  1634).  The  combination  is  a  general  one  and  is 
manifested  by  organic  arsenious  oxides  and  arsines  as  well  as 
by  all  arsenoaryls. 

Recent  German  communications  indicate  that  certain 
'of  these  new  substances,  notably  the  co-ordination  com- 
pounds of  salvarsan  and  neo-salvarsan  with  silver  salts, 
possess  high  therapeutic  value,  the  ratio  of  the  toxic  dose 
to  the  efficient  dose  being  very  much  greater  than  in  the  case 
of  the  parent  arsenobenzene  compound. 

Silver  Salvarsan  (D.  R.  P.  270253). — One  part  of  salvar- 
san dihydrochloride  is  dissolved  in  10  parts  of  methyl 
alcohol  and  the  solution  treated  with  a  methyl  alcoholic 
solution  of  0*36  part  (i  mol.)  of  silver  nitrate.  Addition  of 
ether  precipitates  the  co-ordination  compound,  which  is 
easily  soluble  in  water,  methyl  alcohol  and  glycerol. 

A  compound  containing  two  molecular  proportions  of 
silver  is  prepared  exactly  as  the  above,  but  with  employment 
of  072  part  (2  mols.)  of  silver  nitrate. 

i.  18 


274         ORGANIC  MEDICINAL   CHEMICALS 

Silver  Neo-salvarsan  (D.  R.  P.  268221).— Three  parts 
of  neo-salvarsan  are  dissolved  in  the  smallest  possible 
quantity  of  water  and  treated  with  077  part  of  silver  nitrate 
dissolved  in  20  parts  of  water.  The  solution  is  then  poured 
into  a  mixture  of  alcohol  and  ether,  when  silver  neo-salvarsan 
is  precipitated.  Copper,  gold,  and  other  metallic  derivatives 
are  prepared  similarly.  A  copper  co-ordination  compound 
is  also  produced  when  a  mixture  of  molecular  proportions 
of  sodium-3-amino-4-hydroxyphenyl  arsinate  and  cupric 
chloride  in  aqueous  solution  is  reduced  with  sodium  hydro- 
sulphite.  Reduction  of  the  arsinic  acid  to  the  arsenobenzenc 
compound,  and  formation  of  the  co-ordination  complex 
proceed  consecutively,  and  the  copper  compound,  which  is 
only  sparingly  soluble  in  water,  is  precipitated.  It  is  very 
soluble  in  dilute  hydrochloric  acid,  and  also  in  sodium 
hydroxide. 

LUARGOL  (3  :  3'-diamino-4  : 4'-diliydroxy-arseiiobeiizene 
silver  bromide  antimonyl  sulphate) 

(C12H,202N2As2)2AgBr-SbO(H2S04)2 

I,uargol  is  a  co-ordination  compound  of  a  more  com- 
plex type,  containing  non-ionisable  antimony  as  well  as 
silver.  It  was  introduced  by  Danysz,  who  prepared  it  in 
the  following  manner  (B.  P.  104497/1917). 

One  hundred  grams  of  salvarsan  dihydrochloride  are 
dissolved  in  2500  c.c.  of  distilled  water,  and  the  solution  is 
agitated  for  2-3  hours,  at  I5°-2O°,  with  43  grams  (i  mol.) 
of  freshly  precipitated  silver  bromide.  Antimony  trichloride 
(i  mol.)  52  grams,  is  then  added,  and  dissolved  by  warming 
the  solution,  which  is  then  treated  with  30  grams  of  citric 
acid  dissolved  in  100  c.c.  of  water.  Addition  of  50  grams  of 
pure  concentrated  sulphuric  acid  dissolved  in  250  c.c.  of  water 
then  precipitates  luargol. 

IvUargol  is  an  orange-yellow  powder  containing  20 '6  % 
As  ;  7-4  %  Ag  ;  5-52  %  Br  ;  and  8'iq  %  Sb. 

It  is  insoluble  in  water,  and  for  injection  purposes  is 
dissolved  in  sodium  hydroxide  solution  (0-4  gram  NaOH  to 
i  gram  luargol).  L,uargol  has  been  found  to  be  very  effica- 


ORGANO-METALLIC  COMPOUNDS          275 

cious  in  treatment  of  Trypanasoma  surra  and  Tr.  gambiense, 
and  for  sleeping  sickness  and  syphilis. 

Disodio  Luargol   (Poulenc)  is  readily  soluble  in  water, 
and  is  a  convenient  form  of  administration  of  this  drug. 

GALYL  (4  :  4'  dihydroxy-arsenobenzene-3  :  3'-phosphamic 
acid). 

OH  OH 

OH 


or       II  II 

As_  _,As  As  As 

0NH\PO'OH/NHl 
OH  OH 

Galyl  is  prepared  (E.  P.  9234/1915)  by  condensing  3-amino- 
4  -hydroxyphenyl-arsinic  acid  with  phosphorus  oxy chloride, 
and  reducing  the  resulting  phosphamic  acid  with  sodium 
hydrosulphite.  It  was  introduced  by  Mouneyrat. 

OH 

3-Amino-4-hydroxyphenyl-arsinic    acid 


AsO(OH)2 

Mouneyrat  (E.  P.  3087/1915)  prepared  this  compound  by 
the  electrolytic  reduction  of  3-nitro-4-hydroxyphenyl-arsinic 
acid. 

Twenty  grams  of  the  nitro-acid  are  dissolved  in  400  c.c. 
of  normal  caustic  soda  and  the  solution  placed  in  the  cathode 
compartment  of  an  electrolytic  cell,  the  anode  liquor  being 
15  %  caustic  soda  solution.  The  negative  electrode  is 
mercury,  the  positive  electrode  nickel.  The  cell  is  cooled 
by  immersion  in  cold  water.  A  current  of  2  amps,  at  3^-4 
volts  is  passed  until  a  filtered  portion  of  the  cathodic  liquor 
no  longer  affords  a  precipitate  when  treated  with  an  excess 
of  hydrochloric  acid.  About  5  hours  is  required.  The 
solution  is  then  allowed  to  stand  for  24  hours,  and  neutralised 
exactly,  to  methyl  orange,  with  hydrochloric  acid.  After 
cooling  to  o°  the  precipitated  acid  is  filtered  off  and  purified 


276         ORGANIC  MEDICINAL   CHEMICALS 

by  dissolving  in  dilute  hydrochloric  acid,  decolourising  with 
animal  charcoal,  and  reprecipitating  by  neutralisation  with 
alkali. 

It  can  also  be  prepared  (E.  P.  13485/1910)  by  dissolving 
3-nitro-4-hydroxyphenyl-arsinic  acid,  31  '6  grams,  in  600  c.c. 
of  methyl  alcohol,  adding  840  grams  of  4  %  sodium  amalgam, 
and  digesting  at  6o°-8o°  until  the  evolution  of  gas  has  ceased. 
Part  (450-500  c.c.)  of  the  solvent  is  then  distilled  off,  the 
residue  mixed  with  120  c.c.  of  water,  and  acidified  with 
150  c.c.  of  hydrochloric  acid  (sp.  gr.  I'lg).  After  standing 
for  12  hours  the  solution  is  filtered  from  impurities,  boiled 
with  charcoal,  filtered,  and  neutralised  with  52  c.c.  of  loN. 
caustic  soda,  when  the  bulk  of  the  amino  acid  is  precipitated. 

Jacobs,  Heidelberger  and  Rolf  (/.  Amer.  Chem.  Soc. 
(1918),  40,  1580)  effect  the  reduction  with  ferrous  sulphate 
in  the  following  manner.  Ferrous  sulphate,  440  grams,  is 
dissolved  in  about  1320  c.c.  of  water,  the  solution  chilled  well, 
and  treated,  with  vigorous  stirring  or  shaking,  in  absence 
of  air,  with  25  %  sodium  hydroxide  solution,  until  the  mud 
reacts  strongly  alkaline  to  litmus  paper.  A  solution  of  58*4 
grams  of  3-nitro-4-hydroxyphenyl-arsinic  acid  in  dilute 
caustic  soda  solution  (i  mol.)  is  then  added,  and  the  mixture 
vigorously  agitated  for  five  minutes,  without  heating.  The 
whole  is  then  filtered  and  the  ferric  hydroxide  mud  washed 
with  water.  The  filtrate  is  acidified  with  acetic  acid,  when 
the  amino  acid  crystallises  out.  Yield  80  %. 

4  :  4/-Dihydroxy-arseno-benzene-3  :  s'-phosphamic 
acid.—  "  Galyl,"  3-amino-4-hydroxyphenyl-arsinic  acid,  23.3 
grams,  is  dissolved  in  300  c.c.  of  water  and  90  c.c.  of  caustic 
soda  (36°  Be.).  To  the  solution  are  added  350  c.c.  of  90  % 
alcohol,  after  which  are  introduced  at  o°,  with  cooling  and 
stirring,27  c.c.  of  phosphorus  oxychloride.  The  liquor  is  then 
neutralised  by  the  addition  of  18  c.c.  of  caustic  soda  (36°  Be.) 
and  poured  into  a  solution  of  100  grams  of  crystallised 
magnesium  chloride  and  500  grams  of  sodium  hydrosulphite 
in  1800  c.c.  of  water.  The  mixture  is  heated  for  4  hours  at 
50°,  after  which  the  phosphamic  acid  is  precipitated,  filtered 
off,  washed,  and  can  be  converted  into  the  sodium  salt  by 


ORGANO-METALLIC   COMPOUNDS  277 

being  dissolved  in  sodium  carbonate  and  poured  into  alcohol. 
It  is  dried  in  vacuo  over  sulphuric  acid. 

ORGANIC  ANTIMONY  COMPOUNDS.— Although  most  of 
the  antimony  analogues  of  the  organic  arsenicals  have  been 
prepared,  none  has  yet  been  discovered  that  approaches  in 
specific  therapeutic  effect  the  arsenic  compounds  of  the 
salvarsan  type.  So  far,  only  one  antimony  preparation, 
sulphoform,  has  retained  a  position  in  medicine. 

SULPHOFORM  (Triphenyl-stibine  sulphide)  (C6H5)3SbS. 
383. — Sulphoform  is  prepared  by  treating  triphenyl-stibine 
dichloride,  or  dibromide,  with  ammonium  sulphide. 

Thirty  parts  of  sliced  sodium  are  covered  with  100  parts 
of  dry  benzene,  in  a  cast-iron  vessel  provided  with  a  reflux 
'condenser,  stirring  gear,  and  a  jacket  through  which  can  be 
circulated  either  cooling  water  or  steam.  The  mixture  is 
warmed  to  about  70°,  when  a  solution  of  40  parts  of 
distilled  antimony  chloride  and  60  parts  of  monochlorbenzene 
in  100  parts  of  benzene  is  allowed  to  flow  in,  at  such  a  rate 
that,  without  further  application  of  heat,  the  benzene  is 
kept  gently  boiling  by  the  heat  evolved  by  the  reaction. 
If  it  becomes  violent  the  addition  is  suspended,  and  cold 
water  circulated  through  the  jacket.  When  all  has  been 
added,  the  mixture  is  boiled  for  several  hours  to  complete 
the  interaction.  After  cooling,  the  solution  is  filtered  from 
sodium  chloride  and  unchanged  sodium,  and  the  benzene 
removed  by  distillation.  The  residue,  which  solidifies, 
consists  mainly  of  triphenyl-stibine,  together  with  a  little 
diphenyl-stibine  chloride  and  phenyl-stibine  dichloride.  It 
is  dissolved  in  light  petroleum  and  treated,  whilst  being 
cooled  and  stirred,  with  bromine  (i  mol.).  Triphenyl-stibine 
bromide  (C6H5)3SbBr2  separates  out  in  crystals.  M.p.  216°. 

It  may  be  purified  by  recrystallisation  from  glacial  acetic 
acid. 

3C6H5-f-SbCl3+6Na  ->  (C6H5)3Sb+6NaCl 
(C6H5)3Sb+Br  ->  (C6H5)3SbBr2 

Triphenyl-stibine  sulphide.— Ten  parts  of  triphenyl- 
stibine  bromide  are  dissolved  in  160  parts  of  a  cold  alcoholic 


278         ORGANIC  MEDICINAL  CHEMICALS 

solution  of  ammonia,  saturated  at  room  temperature.  The 
solution  is  filtered  and  treated,  whilst  being  stirred,  with 
purified  hydrogen  sulphide  until  a  permanent  faint  yellow 
colouration  is  obtained.  The  precipitated  crystals  are  filtered 
off,  washed  successively  with  alcohol  and  petroleum,  and  air- 
dried. 

Sulphoform  forms  white  needles,  fusing  at  119°-! 20°.  It 
is  readily  soluble  in  benzene,  chloroform,  and  acetic  acid, 
sparingly  so  in  alcohol,  and  very  slightly  soluble  in  ether, 
petroleum  ether,  or  olive  oil.  Sulphoform  is  employed  in 
treatment  of  skin  diseases  such  as  eczema,  psoriasis,  and 
seborrhoea. 

PROTEIN  COMPOUNDS  CONTAINING  SILVER.— Silver  com- 
pounds are  employed  in  medicine  to  produce  caustic, 
astringent,  germicidal,  and  antiseptic  effects.  For  creating 
caustic  and  astringent  effects  silver  nitrate  is  preferred,  as 
the  organic  compounds  of  silver  are  lacking  in  caustic 
properties.  This  salt,  however,  coagulates  protein,  which 
is  undesirable  when  it  is  necessary  to  create  antiseptic 
conditions.  Irritation  is  thereby  caused  and  the  penetration 
of  the  germicide  is  lessened. 

It  has  been  found  that  soluble  compounds  containing 
silver,  in  which  the  metal  is  non-ionised,  are  produced  by 
digesting  the  insoluble  compounds  which  silver  salts  and 
proteins  form  when  interacted  with  solutions  of  albumoses. 
The  resulting  bodies  possess  the  antiseptic  and  germicidal 
action  of  silver  nitrate  and  are  relatively  non-irritant,  as 
they  do  not  coagulate  protein.  They  are  used  for  treatment 
of  affections  of  the  sensitive  mucous  membranes  of  the 
urethra,  the  eye,  ear,  nose,  and  throat. 

Protargol  is  the  most  generally  used  of  these  silver 
protein  compounds ;  it  contains  8*3  %  Ag.  Others  that 
may  be  mentioned  are  argyrol,  30  %  Ag.  ;  argonin,  4-2  % 
Ag.  ;  albargin,  15-0  %Ag. 

PROTARGOL  (B.  P.  18478/1897).— A  concentrated  aqueous 
solution  containing  4*4  parts  of  protalbumose  is  stirred  into 
a  solution  of  i  part  of  silver  nitrate  in  1*5  parts  of  water. 
The  precipitate  thus  obtained  is  filtered,  washed  with  water, 


ORGANO-METALLIC  COMPOUNDS          279 

and  without  being  previously  dried  is  introduced  into  a 
warm  solution  of  5  parts  of  deutero  albumose  in  4*5 
parts  of  water.  On  heating  at  95°  for  some  time  a  clear 
solution  results  ;  this  is  evaporated  to  dryness  under  reduced 
pressure. 

Protargol  is  a  light-brown  powder,  soluble  in  2  parts  of 
water.  It  should  be  kept  in  well-stoppered  amber  bottles. 

A  i  per  cent,  aqueous  solution  should  give  no  precipitate 
with  alkalis,  sodium  chloride,  or  ammonium  sulphide 
solutions.  The  solution  yields  the  biuret  reaction  when 
mixed  with  an  equal  volume  of  10  per  cent,  caustic  alkali 
and  a  drop  or  so  of  dilute  copper  sulphate  solution.  On 
ignition  a  residue  of  about  8  %  of  metallic  silver  should  be 
obtained.  Protargol  is  successfully  employed  in  treatment  of 
gonorrhoea  and  gonorrhceal  ophthalmia.  It  is  a  powerful 
antiseptic  and  germicide. 

ARGONIN  (E.  P.  22191/1894;  D.  R.  P.  82951).— Three 
kilos  of  the  sodium  salt  of  casein,  containing  no  free  alkali, 
are  mixed  with  300  grams  of  silver  nitrate,  and  the  mixture 
dissolved  in  hot  water.  The  solution  is  then  evaporated 
to  dryness  in  vacuo,  when  a  white  solid  is  obtained  which  is 
soluble  in  water,  giving  a  neutral  reaction.  As  an  alternative 
method  of  procedure  the  aqueous  solution  is  poured  into 
alcohol,  when  the  argonin  is  precipitated. 

Argonin  contains  about  4  per  cent,  of  silver.  It  is  used 
in  the  treatment  of  gonorrhoea  and  in  ophthalmic  practice. 

ORGANIC  MERCURY  COMPOUNDS.— The  great  value  and 
efficiency  of  inorganic  mercury  compounds  in  the  treatment 
of  syphilis  and  as  antiseptics  have  stimulated  a  vast 
amount  of  research  in  order  to  discover  organic  compounds 
of  the  metal  which  should  have  equal  or  greater  antisyphilitic 
properties,  and  which  should  be  free  from  the  many  dis- 
advantages possessed  by  mercury  itself  and  its  inorganic 
derivatives.  Mercuric  salts,  such  as  mercuric  chloride,  have 
an  extremely  high  bactericidal  power.  Their  use,  however, 
is  limited  by  their  high  toxicity  and  the  property  they  possess 
of  coagulating  albumen,  which  causes  them  to  be  extremely 
irritant.  A  further  drawback  is  that  solutions  of  mercury 


280         ORGANIC  MEDICINAL   CHEMICALS 

salts  must  not  be  brought  into  contact  with  metallic 
instruments,  which  otherwise  will  be  attacked,  and  coated 
with  metallic  mercury. 

Mercurous  salts  and  mercury  itself  are  insoluble  in  water 
or  other  media,  and  are  therefore  non-toxic.  Their  physio- 
logical action  depends,  in  all  probability,  upon  the  gradual 
formation  from  them  of  soluble  mercuric  compounds. 
Relatively  large  doses  have  to  be  administered  in  order  to 
register  the  required  therapeutic  effect,  and  it  not  infrequently 
happens  that  a  dose  that  for  the  majority  of  patients  is 
normal  will  produce  in  some,  in  whose  metabolism,  presum- 
ably, the  oxidation  to  mercuric  derivatives  takes  place  with 
abnormal  rapidity,  the  symptoms  of  mercury  poisoning. 

Further,  the  administration  of  these  insoluble  compounds, 
usually  effected  by  intramuscular  injection,  is  often  accom- 
panied by  severe  local  pain.  Remarkably  slight  success, 
however,  has  attended  the  efforts  to  discover  organic  mercury 
derivatives  which  are  therapeutically  effective  and  yet  devoid 
of  the  effects  mentioned. 

Many  compounds,  soluble  in  water  or  an  alkali,  in  which 
the  mercury  is  non-ionised,  have  been  successively  introduced 
into  medicine,  but  almost  without  exception  their  use  has 
been  ephemeral. 

Mercury  salicylate,  almost  the  first  of  this  class  of  com- 
pound to  be  employed,  still  remains  unsuperseded  ;  it  finds, 
however,  only  a  limited  use.  Others  that  may  be  mentioned 
are  :  Mercury  succinimide  (C2H4(CO)2N)2Hg  (Hydrargol)  ; 
Asurol,  a  double  compound  of  mercury  salicylate  and 
sodium  hydroxyisobutyrate ;  Hydrargyrol,  mercury  phenol- 
parasulphonate  ;  Asterol,  a  double  salt  of  Hydrargyrol 
with  ammonium  tartrate  ;  and  Afidol,  the  sodium  salt  of 
oxymercury  ortho-toluic  acid,  the  last  named  substance  being 
employed  as  the  active  constituent  of  a  disinfectant  soap. 


MERCURY    SALICYLATE     C6H4<^CO(^Hg.       336.— One 

molecular  equivalent  of  salicylic  acid,  138  parts,  is  mixed 
with  freshly  precipitated  mercuric  oxide,  216  parts  (i 
mol.)  and  500  parts  of  i  %  acetic  acid  solution.  The 


ORGANO-METALLIC  COMPOUNDS  281 

mixture  is  heated  at  go°-ioo°,  with  continuous  stirring,  until 
the  red  colour  of  the  mercuric  oxide  has  disappeared.  The 
resulting  white  amorphous  precipitate  is  filtered  off,  washed 
with  water,  and  dissolved  in  10  %  caustic  soda  solution, 
about  400  parts  (i  mol.)  of  which  will  be  required.  After 
filtration  the  clear  filtrate  is  treated,  whilst  being  stirred, 
with  dilute  acetic  acid,  when  the  mercury  salicylate  is 
precipitated.  It  is  filtered,  washed,  and  dried,  in  absence 
of  light,  at  a  low  temperature.  Mercury  salicylate  is  a 
white,  or  pinkish-white,  powder,  insoluble  in  water  and  in 
alcohol.  It  dissolves  to  a  clear  solution,  from  which  it  is 
reprecipitated  unchanged  by  acetic  acid. 

Mercury  salicylate  does  not  answer  the  tests  distinctive 
of  mercury  salts.  It  gives  no  precipitate  when  treated  with 
ammonium  sulphide  or  hydrogen  sulphide. 

It  should  afford  no  residue  on  ignition,  and  should  contain 
not  less  than  57-4  %  of  mercury. 

It  is  an  antiseptic  and  antisyphilitic.  It  is  employed 
internally,  being  well  tolerated  by  the  stomach,  and  does 
not  set  up  salivation.  Occasionally,  however,  gastro- 
intestinal irritation  is  produced,  even  when  administered 
by  intramuscular  injection.  Externally  it  is  used  as  a 
dusting  powder,  in  treatment  of  syphilitic  sores  and  certain 
other  diseases  of  the  skin. 

CH2CO  COCH2 

Mercury  Succinimide  |  >N-Hg-N<"       |         376. 

H2CO  COCH2 

— Succinimide,  19*8  parts  (2  mol.),  is  dissolved  in  40  parts 
of  20  %  sodium  hydrate  solution  and  treated  with  a  con- 
centrated aqueous  solution  containing  31*8  parts  of  mercuric 
acetate  (i  mol.).  The  precipitate  which  is  formed  is  dis- 
solved by  boiling,  as  much  more  water  being  added  as  is 
necessary,  the  solution  filtered  and  cooled,  when  mercury 
Succinimide  crystallises  out. 

Alternatively,  19 '8  parts  of  Succinimide  are  heated  at 
100°,  whilst  being  stirred,  with  21*6  parts  of  freshly 
precipitated  mercuric  oxide  and  100  parts  of  water,  until 
the  red  colour  has  disappeared.  Boiling  water  is  then 


282         ORGANIC  MEDICINAL   CHEMICALS 

added  until  the  white  precipitate  has  dissolved,  the  solution 
filtered  and  allowed  to  cool,  and  crystallise. 

Mercury  succinimide  is  a  white  crystalline  powder,  soluble 
in  28  parts  of  cold  water.  The  aqueous  solution  does  not 
precipitate  albumen,  but  the  mercury  is  ionised,  and  reacts 
to  hydrogen  sulphide,  iodides,  and  alkalis.  Mercury 
succinimide  is  employed  in  syphilis,  administered  by 
hypodermic  injection.  It  has  also  been  employed,  with 
good  result,  in  pulmonary  tuberculosis. 


SECTION  X.— THE  DIGITALIS  GROUP,  SKIN 
IRRITANTS,  GLUCOSIDES,  AND  NEUTRAL 
PRINCIPLES 

IN  the  present  chapter  active  natural  glucosides  are 
dealt  with,  of  chief  importance  among  which  is  the  group 
of  heart  tonics  generally  classified  under  digitalis.  The 
plants  commonly  employed  in  medicine  in  this  connection 
are  digitalis,  strophanthus,  and  squill,  but  others  in  less 
use  contain  similar  active  glucosides :  black  hellebore, 
Convallaria  majalis,  Apocynum  cannabinum,  may  be  men- 
tioned, but  there  are  many  others.  The  chemical  examina- 
tion of  these  herbs  has  not  been  satisfactorily  completed, 
though  much  work  has  been  done,  especially  upon  digitalis. 
The  fact  remains,  even  in  this  case,  that  the  most  satisfactory 
medicament  is  the  unpurified  tincture  of  the  drug,  although 
the  latter  is  notoriously  variable  in  its  activity  and  subject 
to  rapid  deterioration.  To  meet  this  difficulty,  physio- 
logically standardised  tinctures  of  digitalis,  strophanthus  and 
squill  are  usually  employed.  The  method  of  physiological 
standardisation  employed  is  based  upon  the  determination 
of  the  minimum  lethal  dose  to  a  frog.  Such  a  criterion 
is  obviously  empirical  and  unsatisfactory,  and  there  is  need 
of  greater  knowledge  of  the  chemical  constituents  of  these 
drugs  and  the  methods  of  administering  them. 

The  therapeutic  use  of  skin  irritants  dates  from  very 
early  times ;  they  are  valuable  in  the  relief  of  pain.  Very 
little  is  known  of  the  rationale  of  their  action.  In  addition 
to  cantharidin  and  oil  of  mustard,  which  are  referred  to 
in  this  chapter,  Rhus  toxicodendron,  or  poison  ivy, 
capsicum,  and  euphorbia  are  employed,  and  many  other 
plants  possess  this  property. 

Cantharidin  and  capsicum  exert  very  marked  blistering 


284         ORGANIC  MEDICINAL   CHEMICALS 

action  upon  the  skin.  j8/3-dichlorodiethyl  sulphide,  employed 
as  a  lethal  "  gas  "  in  the  war  under  the  name  of  "  mustard 
gas/'  possesses  this  blistering  property  in  greater  degree 
than  any  other  known  substance. 


DIGITALIS  AND  ITS  PRINCIPLES 

The  official  digitalis  of  the  British  Pharmacopoeia  con- 
sists of  the  dried  leaves  of  Digitalis  purpurea,  L.,  collected 
from  plants  of  the  second  year's  growth,  as  they  are  com- 
mencing to  flower,  but  the  time  of  collection  does  not 
greatly  affect  their  activity.  Other  species  of  digitalis  are 
active,  especially  the  wild  Spanish  variety. 

Digitalis  is  a  cardiac  and  circulatory  stimulant  and  tonic, 
also  a  diuretic.  It  increases  the  strength  of  the  cardiac 
contractions  and  reduces  the  pulse  rate  without  diminishing 
tension,  acting  directly  on  the  heart  muscle.  It  is  of  great 
value  as  a  heart  stimulant  in  acute  pneumonia,  and  in 
mitral  disease. 

It  is  used  as  a  diuretic  in  cardiac  and  renal  dropsy. 

In  Great  Britain  the  infusion  and  tincture  are  chiefly 
employed.  They  should  be  prepared  from  carefully  dried 
leaves.  Moist  leaves  rapidly  lose  their  activity. 

Infusion  of  Digitalis  is  prepared  from  digitalis  leaves. 
To  60  grains  of  leaves,  in  No.  20  powder,  are  added  20  fl.  oz.  of 
boiling  distilled  water.  The  mixture  is  strained  after  being 
infused  for  15  minutes. 

Tincture  of  Digitalis  is  prepared  by  percolating  2\  parts 
of  dried  digitalis  leaves  with  60  %  alcohol,  to  yield  20  parts. 

The  preparation  of  the  following  partly  purified  principles, 
which  occur  in  commerce,  will  be  described. 

(1)  Digitalin  Nativelle  (crystallised  digitalin). 

(2)  Digitalin  Homolle  (French  digitalin) . 

(3)  Digitalin  Germanicum  (German  digitalin). 

(4)  Digitalin  Verum  (Kiliani). 

(5)  Digitoxin. 

(6)  Gitalin  (Kraft). 

DIGITALIN    NATIVELLE.— One      thousand      grams     of 


THE  DIGITALIS   GROUP,   ETC.  285 

powdered  digitalis  leaves  are  mixed  with  100  grains  of  a 
solution  of  250  grams  of  neutral  lead  acetate  in  a  litre  of 
water.  After  24  hours  the  mass  is  extracted  with  50  % 
alcohol.  The  extract  is  treated  with  a  saturated  aqueous 
solution  containing  40  grams  of  sodium  bicarbonate,  freed 
from  alcohol  by  distillation,  and  concentrated  until  it  weighs 
2000  grams.  When  quite  cold  it  is  diluted  with  an  equal 
volume  of  water.  The  precipitate  is  collected,  suspended  in 
TOO  grams  of  80  %  alcohol,  heated  to  boiling  and  treated  with 
10  grams  of  lead  acetate.  After  cooling,  the  liquor  is  filtered, 
mixed  with  50  grams  of  powdered  animal  charcoal,  freed  from 
alcohol,  evaporated  to  dryness,  and  the  dry  residue  powdered. 
It  is  extracted  exhaustively  with  hot  chloroform,  and,  on 
removal  of  the  solvent,  crude  digitalin  is  obtained.  It 
is  purified  by  being  dissolved  in  100  grams  of  90  %  alcohol, 
treating  the  solution  with  10  grams  of  purified  charcoal 
and  a  concentrated  aqueous  solution  containing  i  gram 
of  lead  acetate,  boiling  for  10  minutes,  filtering,  and  washing 
the  solid  portion  with  alcohol.  From  the  combined  filtrate 
and  washings  the  alcohol  is  removed  completely,  and  the 
residue  is  extracted  with  ether,  in  order  to  remove  fat. 
It  is  then  taken  up  in  8  parts  of  hot  90  %  alcohol,  and  the 
solution  mixed,  after  being  cooled,  with  4  parts  of  ether 
and  8  parts  of  water.  On  standing,  digitalin  crystallises  out 
in  loose  white  glistening  needles. 

Digitalin  Nativelle  is  sparingly  soluble  in  water  and  ether, 
dissolves  easily  in  chloroform.  It  is  stated  to  consist  largely 
of  digitonin,  which  is  devoid  of  "  digitalis  "  action,  but  to 
contain  at  times  much  digitoxin. 

DIGITALIN  HOMOLLE  (amorphous  digitalin). — One  hun- 
dred parts  of  powdered  leaves  are  moistened  with  1000  parts 
of  water,  and  slowly  exhausted,  cold,  in  a  percolator,  until 
3000  parts  of  percolate  have  been  obtained. 

This  is  treated  with  250  parts  of  lead  acetate,  and  the 
filtrate  from  the  resulting  precipitate  freed  from  lead  by 
treatment  with  40  parts  of  crystallised  sodium  carbonate 
and  20  parts  of  sodium  ammonium  phosphate.  After 
filtration,  the  liquor  is  precipitated  with  40  parts  of  tannic 


286         ORGANIC  MEDICINAL  CHEMICALS 

acid.  The  moist  tannate  is  intimately  mixed  with  25  parts 
of  powdered  litharge  and  50  parts  of  purified  animal  char- 
coal, after  which  it  is  dried.  The  dried  mass  is  extracted  with 
90  %  alcohol,  which  dissolves  out  the  digitalin  compounds. 
The  solvent  is  distilled  off,  and  the  residue  washed  with 
water,  after  which  it  is  redissolved  in  alcohol  (90  %),  filtered, 
and  the  solvent  again  removed.  The  residue  is  extracted 
with  chloroform,  and,  on  distilling  off  the  latter,  after 
filtering,  the  digitalin  is  obtained. 

A  yellowish- white  amorphous  powder,  possessing  a 
peculiar  aromatic  odour.  It  is  soluble  in  alcohol  and  chloro- 
form, and  almost  insoluble  in  water  and  ether.  It  is  stated 
to  consist  mainly  of  digitalin,  with  some  digit oxin. 

DIGITALIN  GERMANICUM.— German  digitalin  is  prepared 
from  the  seeds  of  Digitalis  purpurea,  not  from  the  leaves.  An 
alcoholic  extract  is  made,  and  is  treated  with  lead  acetate 
solution.  The  filtrate  is  freed  from  lead  by  means  of  disodittm 
hydrogen  phosphate.  Digitalin  is  precipitated  in  combina- 
tion with  tannic  acid,  and  the  tannate,  after  being  washed, 
decomposed  with  litharge  or  zinc  oxide.  The  solution  is 
evaporated  to  dryness,  and  the  residue  purified  by  crystal- 
lisation from  dilute  methyl  alcohol.  German  digitalin  is 
stated  to  consist  principally  of  digit alein,  with  some  digitalin 
and  digitonin.  It  is  readily  soluble  in  water  and  almost 
insoluble  in  chloroform. 

DIGITALIN  VERUM.— One  part  of  German  digitalin  is 
dissolved  in  4  parts  of  95  %  alcohol.  Five  parts  of  ether 
(720)  are  added,  and  the  mixture  is  allowed  to  stand  in  a 
closed  vessel  for  24  hours.  An  estimation  is  made  of  the 
quantity  of  solid  dissolved  in  the  clear  supernatant  solution, 
and  this,  after  decantation,  is  concentrated  under  reduced 
pressure  until  the  total  weight  is  i  *6  times  that  of  the  dissolved 
portion. 

Water,  2-4  times  the  weight  of  the  dissolved  substance, 
is  added,  and,  on  standing,  digitalin  gradually  separates. 
It  is  filtered  off,  washed  with  10  %  alcohol,  then  with  water, 
and  finally  dried  at  a  moderate  temperature. 

Digitalin     Verum     is     a     white     amorphous     powder. 


THE  DIGITALIS   GROUP,   ETC.  287 

M.p.  217°  It  dissolves  in  1000  parts  of  water,  and  100 
parts  of  50  %  alcohol.  It  is  insoluble  in  ether  and  chloro- 
form. 

DIGITOXIN  CS^H^OH.— Digitalis  leaves  are  lixiviated 
with  cold  water,  filtered,  pressed,  and  extracted  with  50- 
60  %  alcohol.  The  alcoholic  solution  is  precipitated  with 
lead  acetate,  excess  of  lead  being  removed  from  the  nitrate 
by  means  of  ammonia.  The  lead-free  filtrate  is  concentrated 
under  reduced  pressure.  Crude  digitoxin  slowly  crystallises 
out  from  the  residue.  It  is  collected,  dried,  and  redissolved 
in  chloroform,  from  which  it  is  obtained  again  in  a  pure  form 
on  distilling  off  the  solvent.  After  being  washed  with  ether 
it  is  purified  finally  by  crystallisation  from  80  %  alcohol. 

Digitoxin  crystallises  in  pearly  plates  or  needles,  melting 
at  240°.  It  is  readily  soluble  in  alcohol,  less  soluble  in 
chloroform,  very  sparingly  in  ether,  and  insoluble  in  water. 

Digitoxin  is  the  most  toxic  of  the  constituents  of  digitalis, 
and  is  cumulative  in  its  action.  Its  sparing  solubility  and 
the  narrow  difference  between  the  therapeutic  and  the  toxic 
dose  militate  against  its  practical  value.  The  presence  of 
other  glucosides  of  digitalis  increases  its  solubility. 

Digitalin  Nativelle  is  also  said  to  be  a  dangerous 
preparation  on  account  of  the  presence  of  digitoxin. 

GITALIN  C28H48O10. — Powdered  digitalis  leaves  are  ex- 
tracted with  cold  water  and  the  decoction  is  precipitated, 
first  with  lead  acetate,  and  then  with  sodium  phosphate 
solution.  The  clear  filtrate  is  then  treated  with  tannic 
acid  and  the  collected  precipitate  is  decomposed  with  zinc 
oxide,  and  extracted  with  methyl  alcohol.  The  extract 
is  carefully  dried,  dissolved  in  water  and  extracted  with 
chloroform.  Gitalin  crystallises  from  the  concentrated 
chloroform  extract. 

Gitalin  is  a  glucoside  which  affords  digitoxose  and 
anhydrogitaligenin  on  hydrolysis.  It  has  m.p.  I5o°-i55°, 
is  soluble  in  600  parts  of  water,  and  readily  dissolved  by 
most  organic  solvents.  It  is  said  to  possess  to  a  greater 
degree  than  any  other  of  the  digitalis  preparations  the 
characteristic  medicinal  action  of  digitalis.  Digitalis 


288         ORGANIC  MEDICINAL  CHEMICALS 

Homolle  and  Digitalis  Verum  are  also  valued  in  clinical 
practice. 

Digitalin  dissolves  in  concentrated  hydrochloric  or 
sulphuric  acid,  giving  a  golden-yellow  solution,  the  colour 
in  the  latter  case  changing  rapidly  to  blood-red.  On  adding 
to  the  solution  whilst  still  yellow  a  drop  of  either  nitric  acid, 
ferric  chloride,  or  bromine  water,  a  brilliant  purple  coloura- 
tion is  produced. 

Digitoxin  does  not  give  the  colour  reaction  of  digitalin 
with  concentrated  sulphuric  acid. 

If  when  dissolved  in  acetic  acid,  to  which  has  been 
added  i  %  of  a  5  %  solution  of  ferric  sulphate,  there  is 
poured  sulphuric  acid  containing  the  same  quantity  of 
ferric  sulphate  so  as  to  form  a  layer  beneath  it,  a  blue 
colour  is  gradually  developed  in  the  acetic  acid,  whilst  the 
sulphuric  acid  remains  colourless.  None  of  the  other  digitalis 
compounds  affords  this  reaction. 

STROPHANTHUS  AND  STROPHANTHIN.— The  strophanthus 
seeds  of  commerce  consist  of  a  mixture  derived  from  different 
species.  Officially  the  dried  ripe  seeds  of  Strophanthus 
Kombe  are  specified  :  actually  the  S.  Kombe  seeds  of  com- 
merce commonly  are  mixed  with  those  of  5.  hispidus, 
S.  gratus,  etc. 

Strophanthus  Kombe  seeds  yield  from  3  to  4  %  of  ash. 
If  a  section  of  the  seed  be  immersed  in  a  mixture  of  8  parts 
of  sulphuric  acid  (1*84),  and  2  parts  of  water,  a  deep  green 
colour  rapidly  appears  in  the  albumen  surrounding  the 
embryo,  to  which  the  colour  rapidly  extends.  The  galenical 
preparation  of  strophanthus — the  tincture — is  more  widely 
employed  than  its  active  principle — strophanthin,  though 
the  latter  exhibits  the  characteristic  action  of  the  drug  and 
is  soluble. 

Tincture  of  Strophanthus. — One  part  of  strophanthus 
seeds  in  No.  30  powder  is  percolated  with  alcohol,  70  %, 
until  20  parts  are  obtained,  and  diluted  with  alcohol  of  the 
same  strength,  to  yield  40  parts. 

Assay. — A  measured  quantity  of  50  c.c.  of  the  tincture 
is  diluted  with  50  c.c.  of  water  and  the  alcohol  removed  by 


THE  DIGITALIS  GROUP,   ETC.  289 

distillation.  The  filtered  aqueous  liquid,  after  being  shaken 
with  chloroform,  is  digested  for  I  hour  on  a  water  bath  with 
dilute  sulphuric  acid ;  after  cooling,  the  turbid  liquid  is 
agitated  with  3  successive  small  quantities  of  chloroform. 
The  chloroform  extracts  are  transferred  to  a  tared  flask, 
the  solvent  removed  by  distillation,  the  residue  of  stro- 
phanthidin  dried  below  60°  and  weighed.  The  percentage 
of  strophanthidin  found  when  divided  by  0*365  gives  the 
percentage  of  strophanthin  present. 

S.  Kombe  contains  2*3  %  of  strophanthin ;  5.  hispidus 
* '5  to  3-5  %  ;  5.  gratus  about  3-6  %. 

STROPHANTHIN.— The  strophanthin  from  seeds  of  differ- 
ent botanical  species  is  said  to  differ  both  physiologically  and 
chemically.  The  explanation  probably  lies  in  the  fact  that, 
as  prepared  technically,  the  product  is  not  a  pure  substance, 
but  a  mixture  of  glucosides,  the  proportions  in  the  mixture 
as  obtained  from  seeds  of  different  species,  and  possibly  even 
from  the  same  variety  at  different  times,  exhibiting  varia- 
tions. 

Strophanthin  may  be  prepared  by  the  following 
method  : — 

The  powdered  seeds  are  defatted  with  petroleum  ether 
or  carbon  disulphide,  and  extracted  with  alcohol.  The 
solvent  is  removed  from  the  extract  by  distillation,  and  the 
residue  taken  up  with  water.  The  filtered  solution  is  treated 
with  tannic  acid,  when  the  glucosides  are  precipitated  in 
combination  with  this  substance.  The  precipitate  is 
collected,  washed  with  water,  mixed  with  an  excess  of  basic 
lead  acetate,  and  dried  at  a  gentle  heat.  The  dry  mass  is 
extracted  with  alcohol,  the  extract  freed  from  lead  by 
hydrogen  sulphide  and  evaporated.  The  residue  is  crystal- 
lised from  methyl  alcohol,  or  is  dissolved  in  alcohol  and 
precipitated  by  ether. 

Hefter  and  Sachs  (Biochem.  Zeits.  (1912),  40,  83)  proceed 
as  follows  : — 

An  alcoholic*  extract  of  the  seeds  is  prepared,  and  the 
alcohol  removed  by  distillation.  The  residue  is  treated  with 
water  and  the  aqueous  solution  purified  by  precipitation 


290         ORGANIC  MEDICINAL   CHEMICALS 

with  lead  acetate.  The  filtrate  is  freed  from  excess  of 
lead  and  evaporated  to  a  syrup  in  the  presence  of  an 
excess  of  calcium  carbonate.  The  calcium  carbonate  is 
filtered  off  and  the  glucoside  precipitated  by  the  addition 
of  a  large  excess  of  ammonium  sulphate.  It  is  purified  by 
repeatedly  being  dissolved  in  alcohol  and  reprecipitated  by 
ether. 

By  this  procedure  practically  identical  glucosides  have 
been  obtained  from  S.  Kombe  and  S.  hispidus,  the  only 
difference  noted  being  a  slight  one  in  the  optical  rotation. 
By  extracting  the  calcium  carbonate  precipitate,  obtained 
as  above,  with  hot  water,  a  crystalline  glucoside  was  obtained 
from  seeds  of  the  Kombe  plant.  It  possessed  very  similar 
physiological  action  to  that  of  the  amorphous  glucosides, 
differing  only  inasmuch  as  it  possessed  a  slight  hsemolytic 
action ;  and,  like  them,  it  yielded  strophanthidin  on  hydro- 
lysis. Optical  rotation  [a]D  +  287°.  Strophanthin  is  met 
with  as  a  pale  yellow  amorphous  powder  or  in  the  form  of 
microscopic  white  crystals.  M.p.  (anhydrous),  170°. 

It  is  readily  soluble  in  water  and  alcohol,  and  is  practically 
insoluble  in  chloroform,  ether,  petrol-ether,  and  carbon 
disulphide.  No  close  agreement  as  to  the  empirical  formula 
of  strophanthin  has  been  reached,  but  it  is  regarded  generally 
to  be  C4oH5()016. 

The  solution  is  dextro-rotatory  ;  Hefter  and  Sachs  (loc. 
cit.)  give  MD+ 11*87°  f°r  the  glncoside  from  the  Kombe 
plant,  and  [a]  +13*9°  for  that  from  S.  hispidiis. 

Strophanthin  from  5.  gratits  is  sparingly  soluble  in  water 
(i  :  100  at  15°),  fuses  at  i87°-i88°,  and  is  laevo-rotatory. 

Ouabain,  the  active  principle  of  Acocanthera  Schimperi 
(Oliv.),  is  identical  with  strophanthin  from  S.  gratus. 

Strophanthus  is  a  cardiac  tonic.  It  acts  more  energeti- 
cally on  the  heart  than  on  the  vessels,  whereas  digitalis  acts 
on  the  vessels  as  much  as,  or  even  more  than,  on  the  heart. 
Strophanthus  is  therefore  preferred  in  cases  in  which  arterial 
tension  is  already  high,  as  digitalis  increase^  it.  Strophan- 
thus is  valuable  in  mitral  regurgitation,  accompanied  by 
cardiac  insufficiency.  It  acts  with  greater  rapidity  than 


THE  DIGITALIS  GROUP,   E1C.  291 

digitalis,  being  very  soluble  and  diffusible,  and  is  more 
useful  than  the  latter  in  promptly  stimulating  sudden  cases 
of  cardiac  failure.  It  is  not  cumulative,  and,  unless  there  be 
gastro-intestinal  catarrh,  has  no  tendency  to  produce 
digestive  disturbances. 

SQUILL. — Squill  is  the  sliced  dried  bulb  of  Urginea 
Scilla  (Steinh.)  ;  it  is  obtained  from  the  coast  of  the  Mediter- 
ranean. 

Dried  squill  is  very  hygroscopic ;  it  should  be  kept 
thoroughly  dry  in  order  to  preserve  its  medicinal  activity 
unimpaired.  No  active  principle  suitable  for  use  in  medicine 
has  been  isolated  from  squill.  The  chief  preparations 
employed  are  the  tincture  and  the  acetic  acid  extract. 

Tincture  of  Squill  is  prepared  by  macerating  bruised 
squill,  i  part,  with  5  parts  of  60  %  alcohol,  and  straining. 
Acetum  Scillce  results  from  macerating  squill,  I  part,  acetic 
acid,  i  part,  and  water,  3*2  parts. 

The  active  principle  (scillain,  scillitoxin)  is  a  non- 
nitrogenous  glucoside. 

For  its  isolation,  the  disintegrated  dried  drug  is  digested 
for  1-2  days  with  water,  the  extract  is  treated  with  lead 
acetate,  and  after  removal  of  excess  of  lead,  the  filtrate  is  pre- 
cipitated with  tannic  acid.  The  precipitate  is  washed  with 
water,  treated  with  alcohol  and  zinc  oxide  and  evaporated  to 
dryness. 

The  dried  mixture  is  extracted  with  boiling  alcohol,  and 
from  the  extract,  after  removal  of  the  solvent  by  distillation, 
the  glucoside  is  obtained.  The  product  is  a  yellow,  amor- 
phous powder,  possessing  a  bitter  taste.  It  is  readily 
soluble  in  alcohol ;  sparingly  so  in  water,  ether  and  chloro- 
form. It  possesses  a  similar  physiological  action  to  that  of 
digitalin.  Kopaczewski  (Compt.  rend.  (1914),  158,  1520) 
isolated  from  Scilla  maritima  an  active  principle  which  he 
named  Scillitin.  It  melted  at  152°- 154°,  and  was  not 
obtained  crystalline. 

Squill  is  a  stimulant  expectorant,  and  a  diuretic  and 
cardiac  tonic.  It  increases  the  secretion  of  the  bronchial 
mucous  membrane,  and  is  used,  with  other  expectorants,  in 


292         ORGANIC  MEDICINAL  CHEMICALS 

chronic  bronchitis  with  scanty  secretion.  It  is  too  irritant 
for  use  in  acute  bronchitis.  Squill  increases  the  force  of  the 
heart  more  than  either  digitalis  or  strophanthus ;  it  slows 
the  heart  more,  and  causes  more  constriction  of  the  coronary 
vessels.  It  is  preferred  in  cases  where  the  blood  pressure 
requires  to  be  raised. 

SALICIN  CeHnOg-O'CeHi-CHaOH.— Salicin  is  a  glucoside 
of  ortho-hydroxy-benzyl-alcohol,  and  is  found  in  the  bark 
of  various  species  of  Salix,  e.g.,  S.  pentandra,  S.  helix,  S. 
pracox.  S.  nigra  yields  about  07  %  of  salinigrin,  which  is 
the  glucoside  of  meta-hydroxy-benzaldehyde. 

To  prepare  salicin  the  powdered  bark  is  extracted  with 
boiling  water,  the  extract  is  concentrated  in  vacuo  and 
purified  by  precipitation  with  lead  acetate.  After  filtration, 
excess  of  lead  is  removed  from  the  filtrate,  which  is  then 
made  neutral  with  ammonia  and  concentrated  to  a  syrup. 
On  standing,  salicin  slowly  crystallises  out.  It  is  purified 
by  recrystallisation  from  water,  employing  charcoal  as  a 
decolourising  agent.  A  second  crystallisation,  from  alcohol, 
may  be  given  if  necessary. 

Salicin  forms  colourless,  tabular,  or  slender  acicular 
crystals,  possessing  very  little  taste.  M.p.  200°. 

It  dissolves  in  28  parts  of  water  and  in  82  parts  of  alcohol 
(9°  %)•  The  aqueous  solution  is  neutral  towards  litmus. 

Salicin  is  an  antipyretic,  antiperiodic,  tonic  and  bitter 
stomachic.  It  is  better  tolerated  by  the  stomach,  and  is 
less  depressant,  than  sodium  salicylate,  by  which,  however, 
it  has  been  largely  replaced  in  medicine.  Salicin  has  been 
recommended  as  a  prophylactic  against  influenza,  and  for 
its  cure. 

CANTHARIDIN  C10H12O4.  1 9^.— Cantharidin  is  the  active 
principle  of  the  beetle,  Cantharis  vesicatoria,  which  is  found 
in  Spain,  France,  Russia,  Sicily  and  Hungary,  also  of 
Myldbris  phalerata  (Chinese  cantharides),  and  other  species 
of  Mylabris.  The  dried  beetles  contain,  according  to  the 
species,  from  0*6  to  j/o  %  of  cantharidin. 

The  cantharidin  is  extracted  from  the  crushed  beetles 
with  a  solvent,  a  little  hydrochloric  or  acetic  acid  being 


THE  DIGITALIS  GROUP,   ETC.  293 

added  to  liberate  the  cantharidin  from  its  salts.  Benzene  and 
acetone  are  satisfactory  and  cheap  solvents  to  employ.  The 
residue,  after  removing  the  solvent  from  the  extract,  is 
treated  with  petrol-ether,  in  which  cantharidin  is  insoluble, 
to  remove  fatty  substances ;  it  is  then  crystallised  from 
chloroform,  alcohol  or  glacial  acetic  acid. 

Another  method  of  procedure  is  afforded  by  D.  R.  P. 
233467.  Thirty  kilos  of  the  powdered  insects  are  mixed 
with  6  litres  of  absolute  alcohol,  containing  25  %  of  dry 
hydrogen  chloride,  and  the  mixture  allowed  to  stand  at 
below  50°,  with  frequent  agitation.  It  is  then  extracted 
with  a  boiling  mixture  of  5  vols.  of  benzene  and  2 '5  vols. 
of  petrol-ether  (b.p.  5o°-90°).  After  extraction,  the  solvent 
is  removed  at  the  lowest  possible  temperature,  and  the 
mixture  dissolved  in  a  hot  mixture  of  i  vol.  of  absolute 
alcohol  and  9  vols.  of  petroleum  ether.  The  cantharidin 
crystallises  out  after  cooling. 

[With  regard  to  this  process  it  may  be  remarked  that, 
cantharidin  being  a  carboxylic  acid,  it  would  seem  likely 
that  the  foregoing  procedure  would  result  in  part  of  it,  at 
any  rate,  being  transformed  into  its  ethyl  ester.] 

Cantharidin  forms  white,  crystalline  scales.    M.p.  218°. 

It  is  very  slightly  soluble  in  water,  but  dissolves  in  alkalis, 
forming  salts ;  it  is  soluble  in  1150  parts  of  cold  alcohol, 
55  parts  of  chloroform,  and  in  700  parts  of  ether  (rect.). 

It  should  dissolve  without  change  of  colour  in  concen- 
trated sulphuric  acid,  from  which  it  is  precipitated  unchanged 
on  dilution  with  water.  Cantharidin  is  a  powerful  vesicant, 
or  blistering  agent.  It  is  employed  for  treatment  of  deep- 
seated  inflammations,  such  as  in  pleuritis,  pericarditis, 
pneumonia,  sciatica,  etc!";  intenSafly,  in  small  doses,  it  is 
diuretic  and  aphrodisiac. 

OIL  OF  MUSTARD. — Oil  of  mustard  consists  of  not  less 
than  92  per  cent,  of  allyl  isothiocyanate  C3H5CNS.  It  is 
derived  from  the  dried  seeds  of  Brassica  nigra  by  distillation. 
The  latter  contain  a  glucoside,  senigrin,  which  is  hydrolysed 
to  allyl  isothiocyanate  and  a  sugar. 

Allyl  isothiocyanate  may  be  produced  synthetically  by 


294         ORGANIC  MEDICINAL  CHEMICALS 

interaction  of  allyl  iodide  and  potassium  thiocyanate. 
Molecular  quantities  of  the  two  latter  are  dissolved  in  alcohol 
and  water  to  make  a  clear  solution  and  boiled,  using  a  reflux 
condenser,  for  several  hours.  The  reaction  mixture  is  gently 
distilled  to  remove  alcohol,  water  is  added,  and  the  oil 
separated.  Oil  of  mustard  is  a  skin  irritant  employed  as  a 
rubifacient  and  counter-irritant  in  the  relief  of  pain. 
Prolonged  application  causes  vesication. 

THIOSINAMIN  (allyl  thio-carbamate)  C3H5NH'CS'NH2, 
1 1 6,  is  derived  from  allyl  isothiocyanate  by  the  action  of 
alcoholic  ammonia.  It  forms  white  crystals  soluble  in  water,  i 
in  18,  and  in  alcohol,  I  in  2.  It  is  employed  usually  in  con- 
junction with  sodium  salicylate  to  reduce  fibrous  ankylosis 
of  joints  and  for  the  removal  of  fibroid  tissues. 

LECITHIN. — lecithin  is  a  choline  compound  of  stearyl- 
glycero-phosphoric  acid ;  it  is  a  common  constituent  of  animal 
cells  and  of  the  seeds  of  plants.  It  is  of  the  class  of  sub- 
stances, extracted  by  alcohol  from  cells,  generally  termed 
lipoids.  lyipoids  containing  phosphorus  are  called  phos- 
phatides  or  phospholipines. 

Lecithin  is  chiefly  prepared  from  egg  yolk,  but  processes 
have  been  protected  for  extracting  it  from  beans  and  peas 
and  from  the  sprouts  of  germinating  wheat. 

Preparation  of  Lecithin  from  Yolk  of  Egg.— The 
first  practical  method  for  the  isolation  of  lecithin  in  a  reason- 
ably pure  form  was  given  by  Bergell  (Ber.  (1900),  42,  2584). 

The  yolks  (approx.  2 '2  kilos)  of  about  150  eggs  are 
mechanically  separated  and  extracted  for  6  hours  by  boiling 
with  10  litres  of  96  %  alcohol.  The  solution  is  cooled  slowly 
to  o°,  and  treated  with  an  alcoholic  solution  containing 
40  grams  of  cadmium  chloride.  After  being  allowed  to 
stand  for  several  hours,  the  crystalline  precipitate  is  filtered 
off,  washed  with  96  %  alcohol,  air  dried,  and  extracted  with 
ether.  It  is  then  refluxed  with  eight  times  its  weight  of 
80  %  alcohol  and  treated  with  the  correct  quantity  (about  25 
grams)  of  ammonium  carbonate  in  concentrated  solution, 
until  the  liquor  has  a  distinct  alkaline  reaction,  and  the 
filtrate  from  a  test  portion  is  found  to  be  free  from  cadmium. 


THE  DIGITALIS   GROUP,    ETC,  295 

It  is  then  filtered  whilst  hot,  and  the  filtrate  cooled  to 
— 10°.  The  lecithin,  in  the  form  of  a  treacly  substance, 
separates  during  several  hours'  standing.  It  is  isolated  by 
decantation,  washed  by  decantation  with  cold  alcohol,  dis- 
solved in  a  small  quantity  of  chloroform,  reprecipitated 
with  acetone,  and  the  precipitate  filtered  off  and  dried 
in  vacuo.  A  further  quantity  is  obtained  from  the  alcoholic 
solution,  by  distilling  off  the  alcohol,  shaking  out  the 
residue  with  chloroform,  and,  after  washing  the  chloroform 
solution  with  water,  precipitating  the  lecithin  contained 
in  it  with  acetone. 

Yet  more  is  obtained  from  the  ether  extract  of  the 
cadmium  precipitate.  This  is  freed  from  cadmium  with 
ammonium  carbonate,  the  lecithin  isolated  by  freezing  out, 
and  purified  by  precipitation  with  acetone  from  its  solution 
in  chloroform.  The  total  yield  is  5  %  of  the  weight  of  the 
egg  yolk. 

Several  methods  have  been  protected  by  which  the  use 
of  cadmium  chloride  is  avoided. 

In  D.  R.  P.  223593,  ethyl  acetate  is  employed  as  a  solvent. 
One  hundred  kilos  of  egg  yolk  are  shaken,  at  15°,  with 
500  kilos  of  ethyl  acetate.  The  solvent  layer  is  then 
separated,  filtered,  and  concentrated,  the  distillate  being 
used  for  another  extraction  of  the  yolk.  This  is  repeated 
until  the  ethyl  acetate  comes  away  colourless.  The  residue, 
after  removal  of  the  solvent,  is  dried  in  vacuo  until  free  from 
solvent.  It  is  obtained  in  the  form  of  a  powder,  which 
contains  35-40  %  of  lecithin,  and  is  free  from  cholesterin. 

A  pure  lecithin  is  obtained  by  dissolving  the  crude 
product  in  warm  ethyl  acetate  (4O°-7O°),  from  which  it 
crystallises  out  on  cooling.  100  kilos  of  egg  yolk  yield 
9-10  kilos  of  the  purified  lecithin. 

In  D.  R.  P.  260886  it  is  pointed  out  that  lecithin  is 
unstable  at  temperatures  higher  than  50°.  One  hundred 
kilos  of  yolk  of  egg  are  shaken  for  3  hours,  at  atmospheric 
temperature,  with  100  kilos  of  methyl  alcohol.  After 
standing  overnight,  the  solvent  layer  is  filtered,  and  the 
residue  extracted  again  in  the  same  way  with  100  kilos  of 


296         ORGANIC  MEDICINAL  CHEMICALS 

methyl  alcohol.  The  combined  extracts  are  separated 
from  the  fat  which  comes  out  on  standing,  concentrated 
under  reduced  pressure,  and  the  residue  is  dried. 

The  purification  of  crude  lecithin  is  carried  out,  according 
to  D.  R.  P.  291494,  by  washing  twice,  by  prolonged  agitation, 
with  acetone  containing  10-15  %  of  water,  and  to  which 
0*5  to  I  *o  %  of  sodium  bicarbonate  has  been  added,  and  then 
with  pure  acetone  until  it  attains  a  waxy  consistency,  after 
which  it  is  dried  in  vacno  at  a  low  temperature.  A  tasteless 
and  odourless  product  is  obtained  by  this  procedure. 

By  D.  R.  P.  261212,  one  hundred  kilos  of  egg  yolk  are 
mixed  with  500  litres  of  96  %  alcohol  and  shaken  for  24-48 
hours,  at  ordinary  temperature.  The  solution,  after  separa- 
tion and  filtration,  is  mixed  with  one  third  its  volume  of 
a  i  %  to  2  %  solution  of  sodium  chloride.  The  lecithin 
separates  in  a  gelatinous  layer,  mainly  on  the  surface  of  the 
solution,  during  a  long  period  of  standing,  after  which  it  is 
filtered  off  and  dried  at  30°. 

19-20  kilos  of  this  product  (stated  to  be  pure  lecithin) 
are  yielded  by  100  kilos  of  egg  yolk. 

The  Extraction  of  Lecithin  from  Seeds.— (a)  From 
Wheat  Embryo  (D.  R.  P.  179591)  :  Four  parts  of  wheat 
embryo,  dried  at  70°,  are  deprived  of  fat  by  exhaustion  with 
20  parts  of  petrol-ether  (b.p.  55°-57°).  The  mass  is  freed 
from  solvent  and  extracted  completely  with  10  parts  of  hot 
alcohol  (95  %).  A  clear  brown  honey -like  syrup,  which 
contains  lecithin  together  with  proteid  matter,  etc.,  separates. 
Part  of  the  alcohol  is  removed  by  distillation,  and  the  residue 
is  diluted  with  water  until  the  alcohol  content  is  70  %. 
Alcohol  (70  %)  is  added,  if  necessary,  so  that  one  part  of 
extractive  (estimated  by  evaporation  of  an  aliquot  portion) 
is  dissolved  in  10  parts.  The  solution  is  warmed  and  treated 
with  a  hot  10  %  solution  of  barium  chloride  so  long  as  a 
precipitate  continues  to  be  produced.  After  cooling,  the 
crude  lecithin  which  is  precipitated  is  collected  and  purified 
by  solution  in  5  parts  of  chloroform,  filtration  from  insoluble 
matter,  and  removal  of  the  solvent,  preferably  in  vacuo. 

(b)  From  Peas  and  Beans  (D.  R.  PP.  200253,   210013) : 


THE  DIGITALIS   GROUP,   ETC.  297 

One  hundred  kilos  of  dried  shelled  peas  are  boiled  for  4 
hours  with  150  to  200  litres  of  96  %  alcohol.  The  extract, 
after  filtration,  is  concentrated  to  one  half  its  volume,  and 
water  added  to  reduce  the  alcohol  content  to  85  %.  On 
standing,  the  lecithin,  which  is  only  sparingly  soluble  in 
alcohol  of  this  strength,  separates  out  as  a  gelatinous  mass. 
This  is  separated,  washed  with  a  little  cold  96  %  alcohol  in 
order  to  remove  last  traces  of  fatty  and  bitter  principles, 
and  dried  in  vacuo.  i  to  i  J  kilos  are  afforded  by  100  kilos 
of  peas. 

The  lecithin  from  plants,  however,  seems  not  to  be 
identical  with  that  of  animal  origin. 

Lecithin  is  a  translucent,  yellow  or  yellowish-white, 
hygroscopic,  waxy  solid.  It  is  completely  soluble  in  chloro- 
form. 

lecithin  is  employed  to  improve  general  conditions  in 
neurasthenia,  and  generally  as  a  nerve  tonic.  Bain  (Lancet, 
April  6,  1912)  states  that  lecithin  is  a  valuable  drug  in 
anaemia  and  debility  ;  it  acts  as  a  metabolic  stimulus.  Its 
good  effect  on  the  nervous  system  is  attributable  to  improve- 
ment in  general  nutrition  and  not  to  its  being  a  good  "  brain- 
food/'  Its  most  striking  effect  is  on  the  blood,  red  and  white 
corpuscles  (especially  lymphocytes)  and  haemoglobin  being 
all  increased.  With  phytin  (plant  lecithin),  on  the  other 
hand,  unsatisfactory  results  were  obtained. 

a-  AND  J3-GLYCEROPHOSPHORIC  ACID 

CH20'PO(OH)2  CH2OH 

I  I 

CHOH  and     CHO'PO(OH)2 

I  I 

CH2OH  CH2OH 

The  following  salts  of  glycerophosphoric  acid  are  employed, 
as  well  as  the  acid  itself,  in  medicine  :  sodium,  calcium, 
potassium,  magnesium  and  iron  glycerophosphates.  The 
sodium  salt,  moreover,  is  met  with  in  two  varieties,  a  hand- 
somely crystalline  compound  containing  5  molecules  of 
water  of  crystallisation,  and  a  syrup  containing  50  %  or 
75  %  of  anhydrous  sodium  glycerophosphate. 


298          ORGANIC  MEDICINAL   CHEMICALS 

Two  isomeric  glycerophosphoric  acids,  a  and  £,  can  exist, 

CH2OPO(OH)2  CH2OH 

I  I 

CHOH  and     CHO'PO(OH)o 

I  I 

CH2OH  CH2OH 

a-glycerophosphoric  acid.  /3-glycerophosphoric  acid. 

of  which  the  a  variety,  containing  an  asymmetric  carbon 
atom,  can  exist  in  two  stereo-isomeric  forms,  Isevo  and  dextro. 

"  Natural "  glycerophosphoric  acid,  derived  from  egg 
lecithin,  exhibits  optical  rotation,  therefore  must  consist, 
at  least  partially,  of  the  a  acid. 

Two  processes  are  employed  technically  for  the  synthesis 
of  glycerophosphoric  acid.  One  consists  in  heating  glycerine 
and  phosphoric  acid  together  at  a  temperature  of  ioo°-io5° 
and  has  been  shown  to  afford  mainly  the  a  acid ;  by 
the  other  method  mono-sodium  phosphate  is  heated  with  two 
molecular  proportions  of  glycerol,  and  the  resulting  diglyceryl 
ester  hydrolysed  with  sodium  hydroxide. 

NaO-PO(OH)2+2C3H8O3    ->    NaO-PO(OC3H7O2)2 

->     (NaO)2PO-0-C3H702 

A  considerable  portion  of  a  crystalline  sodium  salt  is 
obtainable  by  this  process,  and  this  has  been  shown  to  be 
sodium  jS-gly  cerophosphate .  The  liquor  from  which  no  further 
quantity  of  this  crystalline  salt  can  be  obtained,  constitutes 
the  liquid  sodium  glycerophosphate  of  commerce,  whilst 
the  other  salts,  calcium,  magnesium,  iron,  etc.,  and  the  acid 
itself,  are  most  generally  prepared  from  the  product  of  the 
interaction  of  phosphoric  acid  and  glycerin. 

Another  method  (B.  P.  2883  of  1912)  consists  in  heating 
monochlorohydrin,  C3H6O2C1,  with  phosphoric  acid. 

Pure  a-glycerophosphoric  acid  has  been  prepared  (King 
and  Pyman,  Trans.  C.  S.  105,  1253)  by  the  interaction  of 
a-monochlorohydrin  and  trisodium  phosphate,  and  the  pure 
j8  acid  by  the  interaction  of  a-dichlorohydrin  with  phosphoryl 


THE  DIGITALIS  GROUP,   ETC.  299 

chloride,  converting    the  product,  bis- s-dichloro-iso-p ropy  1 
phosphoric  acid,  into  its  calcium  salt, 

{(CH2C1)2  :CHO}2  PO-0-Ca-0-PO{0-CH  :  (CH2C1)2}2-4H2O 

and  hydrolysing   this  by   boiling   with  sodium  carbonate 
solution,  when  sodium  jS-glycerophosphate  is  produced. 

Preparation  from  Glycerine  and  Phosphoric  Acid.— 
A  mixture  of  25  parts  of  glycerine  and  30  parts  of  66  %  phos- 
phoric acid  (sp.  gr.  1/70)  is  heated  at  105°.  Power  and  Tutin 
(Trans.  Chem  Soc.  (1905),  249)  heated  for  24  hours  (three 
periods  of  8  hours)  ;  Prunier  (Bull.  Soc.  Chim.  (1907),  [4]  1046) 
heated  equal  weights  of  glycerine  and  60  %  acid  at  110°  for 
70-80  hours.  The  reaction  mass  should  be  stirred,  in  order 
to  prevent  local  overheating.  The  product  is  blown  into 
600  parts  of  water  containing  30  parts  of  slaked  lime,  and 
stirred  until  neutral.  The  solution  is  filtered,  through  a 
filter  press,  at  i6°-i8°,  at  which  temperature  the  calcium  salt 
is  most  soluble,  and  the  residue  washed  with  water  until 
the  washings  no  longer  afford  a  precipitate  when  heated  to 
100°.  The  combined  filtrates,  which  contain  the  calcium 
glycerophosphate  in  solution,  are  neutralised  (to  phenol- 
phthalein)  with  a  solution  of  glycerophosphoric  acid,  and 
evaporated  nearly  to  dryness,  preferably  under  diminished 
pressure.  After  cooling,  alcohol  is  added,  and  the  whole 
filtered.  The  filtrate  contains  the  excess  of  glycerine  and 
any  colouring  matter  that  has  been  produced.  The  alcohol 
and  glycerine  are  recovered  by  distillation  and  used  again. 

The  calcium  glycerophosphate  is  washed  with  a  little 
alcohol  and  dried.  In  order  to  obtain  the  free  acid,  from 
which  the  other  salts  are  prepared,  a  weighed  quantity  of 
the  calcium  salt,  in  which  the  percentage  of  calcium  has  been 
accurately  determined,  is  mixed  with  water  and  treated 
with  the  theoretically  required  amount  of  sulphuric  acid. 
After  filtration  from  the  precipitated  calcium  sulphate, 
a  solution  of  barium  glycerophosphate  is  added,  exactly 
sufficient  to  precipitate,  as  barium  sulphate,  the  dissolved 
sulphate  ions.  The  filtered  solution  is  then  concentrated 
to  sp.gr.  1*127,  if  glycerophosphoric  acid  itself  is  required,  or 


300         ORGANIC  MEDICINAL  CHEMICALS 

neutralised  with  precipitated  ferric  hydroxide,  magnesia, 
or  potash.  Addition,  before  or  during  neutralisation,  of 
the  quantity  of  oxalic  acid  necessary  to  combine  with  the 
calcium  still  remaining  in  the  solution,  will  result  in  the 
removal  of  this  impurity.  The  respective  salts  are  then 
obtained  by  evaporation. 

Preparation  from  Sodium  Dihydrogen  Phosphate 
and  Glycerine. — According  to  Poulenc  Frere's  original 
patented  method  (D.  R.  P.  208700),  by  which  crystalline 
sodium  /3-glycerophosphate  is  prepared,  i  molecular  equi- 
valent of  sodium  dihydrogen  phosphate  and  2  equivalents 
of  glycerin  are  heated  in  vacuo. 

/OH  /OC3H702 

0=PeOH  +2C3H803    ->    O=P^-OC3H702+2H20 
xONa  xONa 

The  resulting  product,  sodium  diglycero-phosphate,  is 
hydrolysed  by  being  boiled  with  sodium  hydroxide  solution. 

/OC3H702  X)C3H702 

0=P^OC3H702+NaOH    ->    O=P^ONa        -fC3H8O3 
xONa  xONa 

The  solution  is  then  concentrated  and,  after  cooling, 
sodium  glycerophosphate  crystallises  out.  By  a  variation 
of  the  above,  ammonium  acid  phosphate  is  used  in  place 
of  the  sodium  salt. 

No  details  are  furnished  in  the  specification  as  to  the 
temperature,  or  time  of  heating.  These  are  supplied,  how- 
ever, by  Wulfmg,  who  evades  the  above  patent  by  employing, 
instead  of  sodium  dihydrogen  phosphate,  a  mixture  of 
disodium  hydrogen  phosphate  and  meta-phosphoric  acid 
(D.  R.  P.  205579). 

One  part  of  glacial  metaphosphoric  acid  is  mixed  with 
i '4  parts  of  disodium  hydrogen  phosphate  and  3*2  parts 
of  glycerine.  The  mixture  is  heated  under  a  vacuum  of 
about  50  mm.,  and  the  temperature  gradually  raised  from 
120  to  210°,  at  which  it  is  kept  until  a  test  portion  gives 
a  negative  reaction  for  phosphoric  acid.  The  reaction  mixture 


THE  DIGITALIS  GROUP,   ETC.  301 

is  then  hydrolysed  with  caustic  soda.  The  composition  of 
the  metaphosphoric  acid  employed  in  this  example  is  given 
as  Na =14-04  %  ;  HPO3  (free)  =  31-68  % ;  HPO3  (combined) 
=  52-8  %;  H20  =  2-4  % 

In  a  subsequent  patent  (D.  R.  P.  217553),  in  which  a 
further  variation  is  described,  it  is  stated  that  the  temperature 
given  above  is  unnecessarily  high,  and  that  the  reaction  can 
be  carried  out  advantageously  at  145°.  One  hundred  parts 
of  meta-phosphoric  acid  and  17  parts  of  sodium  hydrate 
are  mixed  with  60  parts  of  water  and  100  parts  of  glycerin 
(sp.  gr.  1*23)  and  heated  in  vacuo.  The  water  distils  over 
at  70°,  and  at  125°  solution  is  complete.  The  reaction  is 
finished  at  145°,  when  the  product  is  treated  as  before. 

The  reaction  mixture,  after  hydrolysis,  contains,  as  seen 
from  the  equations,  sodium  glycerophosphate  together  with 
a  molecular  equivalent  of  glycerine.  This  requires  to  b.e 
recovered,  and  by  doing  so  the  subsequent  crystallisation 
of  the  salt  is  facilitated.  This  is  effected  by  concentrating, 
in  vacuo,  to  a  syrup,  and  boiling  out  with  strong  alcohol, 
in  which  the  glycerine  dissolves.  After  separation  of  the 
alcohol-glycerine  layer,  the  residue  is  set  aside  to  crystallise, 
and  allowed  to  stand  until  the  process  is  complete.  Crystals 
and  liquid  are  then  separated  by  centrifugal  action  or 
rrydraulic  pressure.  The  former  are  purified  by  recrystallisa- 
tion  from  water ;  the  latter  is  adjusted  to  the  required 
strength  and  marketed  as  "  Sodium  glycerophosphate 
liquor,"  50  %  or  75  %. 

Another  process  that  has  been  proposed  (D.  R.  P. 
242422)  for  the  production  of  glycerophosphoric  acid  consists 
in  generating  phosphoric  acid  in  situ  by  treating  calcium 
phosphate  with  sulphuric  acid  and  heating  the  mixture  with 
glycerine. 


SECTION  XI.— OTHER  SUBSTANCES  OF  IN- 
TEREST—PITUITARY AND  THYROID 
EXTRACTS,  VITAMINES,  SACCHARIN 

PREPARATIONS  of  pituitary  and  thyroid  glands  exhibit 
marked  pharmacological  properties,  and  their  medicinal 
application  has  acquired  outstanding  importance  compared 
to  that  of  the  preparations  of  other  animal  glands,  such  as 
duodenal  gland,  thymus  gland,  ovaries,  testicles,  and  brain 
and  spinal  cord,  to  none  of  which  can  so  far  be  ascribed 
characteristic  physiological  effects. 

The  wide  application  of  pituitary  extract  in  obstetrics 
and  of  thyroid  in  the  treatment  of  myxcedema  and  cretinism 
was  thought  to  call  for  a  reference  to  the  methods  of  prepara- 
tion of  these  substances,  albeit  that  we  have  but  little 
chemical  knowledge  of  them. 

The  latter  statement  also  applies  to  the  vitamines  or 
accessory  food  substances,  the  present  state  of  our  knowledge 
of  which  is  derived  almost  exclusively  from  physiological 
as  distinct  from  chemical  experiments.  Their  use  in  medical 
treatment  and  dietetics  is  very  rapidly  gaining  ground. 

Saccharin,  on  the  other  hand,  is  a  substance  of  which  the 
chemistry  is  well  known,  but  which  is  entirely  without  physio- 
logical action  apart  from  its  intensely  sweet  taste.  Its  use  as 
a  sweetening  agent  where  sugars  are  contra-indicated 
gives  it  a  place  of  importance  in  medicine  despite  its 
inactivity. 

PITUITARY  GLAND.— The  pituitary  gland  of  mammals— 
a  small  ductless  gland  situated  at  the  base  of  the  brain — 
contains  in  its  posterior  or  infundibular  lobe  a  substance 
which  exerts  powerful  physiological  activity.  The  anterior 
lobe,  or  hypophysis,  is  not  possessed  of  the  same  action,  but 


OTHER  SUBSTANCES   OF  INTEREST       303 

exercises  an  obscure  controlling  action  upon   development 
and  metabolism. 

The  infundibular  portions  of  the  glands  of  sheep,  oxen, 
or  pigs  possess  similar  activity.  Any  of  these  sources  of  the 
glands  may  therefore  be  employed  in  the  preparation  of  the 
extract.  The  gland  being  an  exceedingly  small  one,  ox 
glands  repay  best  the  labour  of  dissection.  The  dried,  dis- 
sected whole  gland  is  occasionally  administered  internally  to 
improve  metabolism,  but  its  administration  is  not  attended 
with  any  obvious  results.  On  the  other  hand,  extracts  of  the 
posterior  lobe  injected  intramuscularly  or  intravenously  exer- 
cise a  pronounced  action  on  many  organs,  causing  prolonged 
rise  in  blood  pressure  and  a  strengthening  of  heart  beat. 
They  also  stimulate  peristalsis,  diuresis,  contraction  of  the 
uterus,  milk  secretion,  etc.  See  Oliver  and  Schafer  (Journ. 
Phys.  xviii.  p.  277) ;  Magnus  and  Schafer  (Ibid,  xxvii.) ; 
Dale  (Biochem.  Journ.  iv.  p.  427). 

Extract  of  Pituitary  Gland.— The  finely  minced  fresh 
or  dried  posterior  lobe  in  weighed  amount  is  added  to 
distilled  water  acidified  by  acetic  acid— 0-5  %,  the  tempera- 
ture is  raised  to  the  boiling  point,  and  the  boiling  continued 
for  ten  minutes.  This  operation  may  best  be  done  in  a 
hard-glass  flask.  The  solution  is  set  aside  to  cool  and  allowed 
to  stand  for  at  least  twenty-four  hours,  care  being  taken  to 
exclude  bacteria.  It  is  then  filtered,  made  up  to  the  required 
volume,  again  sterilised  by  heating  to  90°,  and  allowed  to 
stand.  The  process  is  a  perfectly  simple  one  and,  under 
conditions  of  ordinary  care,  little  or  no  loss  of  activity 
takes  place.  It  is  important  to  avoid  the  alkaline  condition, 
traces  of  hydrogen  peroxide  will  cause  a  loss  of  activity,  and 
a  rapid  loss  of  activity  will  also  occur  if  organisms  be  allowed 
to  develop  in  the  solution,  or  if  proteolytic  enzymes  or  other 
hydrolytic  agencies  be  at  work. 

Proposals  have  been  made  to  precipitate  albuminous 
matter  by  the  addition  of  uranium  acetate  or  dialysed  iron, 
but  these  constitute  no  improvement  and  are  apt  to  result 
in  a  loss  of  activity  possible  through  adsorption  of  the  active 
substance  by  the  precipitate. 


304         ORGANIC   MEDICINAL   CHEMICALS 

No  chemical  method  of  testing  the  activity  of  the 
extract  has  been  devised,  nothing  being  known  of  the 
chemical  nature  of  the  active  ingredient,  which,  however, 
can  be  removed  from  the  extract  by  dialysis  and  appears 
to  be  of  a  comparatively  simple  nature.  The  extract  is 
made  in  different  strengths  ;  a  solution  representing  20  %  of 
its  weight  of  fresh  gland  is  that  commonly  employed.  It  is 
not  official  in  the  British  Pharmacopoeia,  but  the  United 
States  Pharmacopoeia  includes  an  extract.  This  is  stan- 
dardised by  a  physiological  method,  to  represent  about  13  % 
of  fresh  gland.  The  physiological  standard  there  proposed 
is  that  i  c.c.  diluted  20,000  times  with  Ringer's  solution  has 
the  same  activity  on  the  isolated  uterus  of  the  virgin  guinea 
pig  as  a  I  in  20,000,000  solution  of  Histamine  hydrochloride. 
It  has,  however,  been  pointed  out  that  this  standard  is  unsuit- 
able and  considerably  below  that  of  commercial  solutions  in 
common  use.  The  above  method  is  based  on  the  method  pub- 
lished by  Dale  and  I/aidlaw  (Journal  of  Pharmacology,  iv.  75), 
who,  however,  adopt  as  their  standard  an  extract  prepared 
from  perfectly  fresh  infundibular  substance,  which  has 
been  preserved  and  sterilised  in  sealed  glass  phials.  Under 
such  conditions  they  find  the  extract  has  great  stability. 

The  determination  by  means  of  the  contraction  of  the 
uterus  of  the  virgin  guinea  pig  has  been  found  a  more  accurate 
method  of  evaluation  than  methods  dependent  upon  the 
action  on  the  blood  pressure  or  on  diuresis. 

Pituitary  extract  is  used  chiefly  in  medicine  as  a  remedy 
for  secondary  weakness  of  uterine  contraction,  and  is  of 
special  value  in  assisting  labour  at  child-birth.  It  is  employed 
in  surgical  shock  and  collapse  after  severe  operations  and 
serious  loss  of  blood,  also  to  restore  activity  to  the  para- 
lytically  distended  bowel  in  certain  conditions  and  to  produce 
diuresis.  Paradoxically  it  controls  the  diuresis  of  Diabetes 
insipidus.  For  a  few  hours  after  a  full  dose  has  been  admin- 
istered further  doses  have  no  effect. 

THYROID  GLAND.— The  thyroid  gland  is  a  ductless  gland 
situated  in  the  throat ;  its  secretions  are  essential  to  normal 
metabolism.  Various  diseases  result  from  the  failure  of  this' 


OTHER  SUBSTANCES  OF  INTEREST       305 

gland  to  function  properly.  On  the  other  hand,  an  excessive 
thyroid  secretion  appears  to  be  at  least  a  factor  in  the  causa- 
tion of  exophthalmic  goitre  or  Graves'  disease.  Thyroid 
deficiency  is  generally  met  by  the  administration  of  the  gland 
itself,  but  an  extract  may  be  prepared  which  has  the  same 
effect.  The  dried  gland,  however,  is  characterised  by  great 
stability,  and  consequently  but  little  advantage  is  gained  by 
the  use  of  an  extract. 

The  glands  are  generally  obtained  from  the  sheep  ;  in  this 
species  one  pair  of  the  small  glands,  known  as  the  parathyroid 
glands,  is  incorporated  in  the  lobes,  and  these  are  stated  to 
secrete  a  substance  which  acts  powerfully  upon  the  nervous 
system.  To  prepare  the  dried  thyroid  the  total  gland  is 
dissected  from  the  surrounding  fat  and  tissues,  minced  and 
salted.  It  is  then  carefully  and  thoroughly  dried,  either  in 
a  current  of  warm  air  or  in  a  vacuum  cupboard,  at  a  tempera- 
ture not  exceeding  40°.  The  dried  glands  are  finely  powdered. 
They  are  commonly  administered  in  tablet  or  cachet  form. 

The  active  principle  being  a  substance  containing  a 
considerable  percentage  of  iodine,  the  activity  of  the  gland 
may  be  tested  by  a  determination  of  the  combined  iodine 
content,  which  should  be  about  0-2  %. 

The  British  Pharmacopoeia  gives  a  method  for  the 
preparation  of  a  lyiquor  Thyroidei,  and  the  British  Pharma- 
ceutical Codex  one  for  an  Kxtractum  Thyroidei.  They  are 
simple  pharmaceutical  processes  which  do  not  call  for 
comment.  Recently  Kendall  (Journ.  Biolog.  Chem.  xxxix. 
125  and  xl.  265)  has  isolated  from  the  thyroid  a  pure 
crystalline  substance,  Thyroxin,  possessing  the  characteristic 
physiological  activity  of  the  glands  ;  the  following  is  the 
method  of  preparation. 

Preparation  of  Thyroxin. — Fresh  or  desiccated  thyroid 
gland  is  treated  in  an  enamelled  vessel  for  24  hours  with 
hot  5  %  aqueous  sodium  hydrate  solution.  The  insoluble 
soaps  are  separated  by  filtration,  and  the  filtrate  acidified 
after  being  cooled.  The  precipitate  thus  formed  comprises 
i  %  of  the  total  weight  of  the  fresh  glands  used,  and  con- 
tains 26  %  of  iodine.  It  is  redissolved  in  caustic  soda  and 
i.  20 


306         ORGANIC  MEDICINAL  CHEMICALS 

reprecipitated  with  hydrochloric  acid.  It  is  then  air- 
dried,  dissolved  in  alcohol  95  %  and  made  neutral  to  litmus 
with  sodium  hydroxide.  The  solution  is  then  filtered  and 
the  filtrate  treated  with  a  hot  concentrated  aqueous  solution 
of  baryta;  after  a  further  filtration  a  small  quantity  of 
sodium  hydrate  is  added,  and  carbon  dioxide  passed  through. 
The  precipitated  barium  and  sodium  carbonates  are  removed 
and  the  alcohol  distilled,  the  last  traces  being  removed  by 
evaporation  'in  an  open  dish.  The  residue  is  acidified  with 
hydrochloric  acid,  the  precipitate  filtered  off  and  dissolved 
in  alkaline  (NaOH)  alcohol.  The  solution  is  next  treated 
with  carbon  dioxide,  and  after  removing  the  sodium  carbonate 
the  alcohol  is  again  removed  by  distillation.  On  standing 
the  mono-sodium  salt  of  thyroxin  separates.  It  is  subjected 
to  further  precipitation  by  a  repetition  of  the  above  treatment 
and  by  being  several  times  dissolved  in  alkaline  alcohol 
and  precipitated  with  acetic  acid.  By  this  method,  6550 
pounds  of  fresh  hog's  thyroid  gland  yielded  33  grams  of 
thyroxin. 

The  following  formula  has  been  assigned  by  Kendall  to 
thyroxin  : 

HI 

CH—  COOH 


H     N 
H 

It  is  a  colourless,  odourless,  crystalline  substance,  existing 
in  four  distinct  forms,  the  keto  —  m.p.  250°,  the  enol  —  m.p. 
204°,  open  ring  —  m.p.  225°,  and  a  tautomericform  —  m.p.  216°. 
It  contains  65  %  of  iodine  ;  it  is  insoluble  in  aqueous 
solutions  of  all  acids.  With  alkali  hydroxides  it  forms 
dibasic  salts,  with  alkali  carbonates  monobasic  salts.  Its 
acetyl  and  dimethyl  derivatives  have  been  prepared  and 
the  presence  of  an  indol  ring  recorded  ;  the  constitutional 
formula  given  above  requires  further  confirmation. 

Thyroid  medication  is  chiefly  employed  in  the  treat- 
ment of  diseases  resulting  from  deficient  conditions  of  the 


OTHER  SUBSTANCES  OF  INTEREST        307 

thyroid  gland,  for  instance  in  myxoedema  and  cretinism ; 
the  dried  substance  in  tablets  or  cachets  is  generally  employed. 
The  administration  is  continued  often  for  long  periods,  and 
frequently  throughout  life. 

The  myxcedematous  patients  possess  generally  a  uniform 
metabolic  rate  which  is  about  40  %  below  normal.  Adminis- 
tration of  I  mg.  of  thyroxin  has  been  shown  to  produce, 
in  an  adult  weighing  150  Ibs.,  an  increase  of  2  %  in  the 
metabolic  rate.  The  curve  of  this  response  is  approximately 
a  straight  line  between  30  %  below  normal  to  15-20  %  above 
normal  metabolic  rate,  and  it  is  possible  by  such  medication 
to  maintain  the  metabolic  rate  at  any  desired  figure  between 
these  limits,  over  periods  of  time  measured  in  years. 

Thyroxin  is  not  essential  to  life,  and  in  its  complete 
absence  the  fundamental  chemical  reactions  occur  and  life 
is  maintained,  but  the  flexibility  of  energy  output  is  limited 
to  a  narrow  range.  It  has  been  found  that  in  the  winter 
months  the  thyroid  glands  of  oxen,  sheep  and  pigs  contain 
less  thyroxin,  as  measured  by  the  iodine  content,  than  in 
summer,  and  this  is  held  to  be  attributable  to  the  fact  that 
the  greater  amount  of  energy  required  to  be  exerted  during 
cold  weather  to  maintain  body  temperature,  causes  a  wearing 
out  of  the  thyroid  reserves,  consumption  being  greater  than 
production.  With  the  advent  of  the  warmer  seasons  the 
reverse  process  sets  in  and  the  thyroxin  store  is  again 
built  up. 

VITAMINES.—-Vitamines  are  substances— the  existence  of 
three  is  recognised  with  certainty — whose  presence  in  the 
dietary  is  essential  for  proper  nutrition,  and  whose  absence, 
if  prolonged,  gives  rise  to  serious  disease,  such  as  rickets, 
scurvy,  and  beri-beri.  little  is  known  as  to  their  chemical 
nature ;  in  fact,  no  vitamine  has  yet  been  isolated  in 
a  state  approaching  purity.  Recognition  of  the  vitamine 
principle  arose  out  of  a  study  of  the  etiology  of  beri-beri. 
This  disease  is  endemic  among  populations  whose  main 
article  of  diet  is  rice.  The  arrival  in  the  East  of  modern 
milling  machinery  brought  about  a  great  increase  in  the 
number  of  cases,  and  in  1897  evidence  was  brought  forward, 


ORGANIC  MEDICINAL  CHEMICALS 

by  Eijkmann,  that  beri-beri  was  related  to  the  kind  of 
rice  consumed.  Statistics  were  collected  showing  the  inci- 
dence of  beri-beri  in  the  Dutch  Bast  Indian  prison  establish- 
ments. Different  gaols,  owing  to  different  situations  and 
local  customs,  were  supplied  with  different  kinds  of  rice. 
In  thirty-seven  prisons  red  rice  was  employed,  and  only  one 
of  these  developed  cases  of  beri-beri ;  in  thirteen  prisons  in 
which  a  mixture  of  red  and  white  rice  was  given,  six  of  them 
developed  the  disease  ;  whilst  of  fifty-one  prisons  where 
white  rice  alone  was  eaten,  in  no  fewer  than  thirty-six  was 
beri-beri  developed. 

In  1907-8  Fraser  and  Stanton  carried  out  experiments 
in  which  disturbing  factors,  such  as  the  possibility  of  the 
conveyance  of  an  infection,  were  eliminated  or  were  ade- 
quately controlled.  One  half  of  a  gang  of  300  Javanese 
labourers  was  fed  on  white  rice  and  the  other  half  on  par- 
boiled rice.  In  about  three  months  cases  of  beri-beri  began 
to  occur  among  those  fed  on  white  rice,  whilst  no  sign  of  the 
disease  appeared  amongst  the  others.  The  conditions  were 
then  reversed,  and  again  the  disease  developed  only  among 
the  party  partaking  of  white  rice  Continuing  their  re- 
searches these  investigators  showed  that  the  disease  is 
caused  by  the  deficiency  in  polished  rice  of  a  substance, 
contained  in  the  outer  layers,  that  is  removed  in  the  milling 
process.  This  substance  was  found  to  be  soluble  in  water 
and  alcohol.  It  is  stable  in  neutral  or  acid  solutions,  but  is 
destroyed  by  alkali.  Heating  at  120°  for  2  hours  completely 
destroys  it. 

It  was  soon  shown  that  vitamines  were  not  contained  only 
in  rice  polishings,  but  were  present  in  many  other  substances 
of  vegetable  and  animal  origin.  Funk,  Edie,  and  others 
proved  their  existence  in  yeast,  milk,  and  bran ;  the  list 
has  been  extended  to  include  wheat,  oats,  nettles,  blood, 
yolk  of  eggs,  cabbage,  potatoes,  meat,  and  other  substances. 

Three  classes  of  vitamine,  having  different  actions,  are 
now  recognised.  The  antineuritic  vitamine,  which  prevents 
and  cures  polyneuritis,  or  beri-beri,  is  known  as  the  Water- 
soluble  B  vitamine.  It  occurs  in  greatest  quantity  in  rice 


OTHER  SUBSTANCES  OF  INTEREST   309 

polishings,  wheat  embryo,  and  yeast,  and  is  present  also  in 
lean  meat,  milk,  egg  yolk,  cabbage,  potatoes,  etc. 

Another,  known  as  Fat-soluble  A,  is  anti-rachitic,  that  is 
to  say,  its  presence  in  the  dietary  is  essential  if  the  develop- 
ment of  rickets  in  children  is  to  be  prevented.  This  body 
is  contained,  in  largest  amount,  in  cod  liver  oil,  butter,  and 
3^olk  of  egg  ;  to  a  lesser  extent  in  wheat  embryo  and  cabbage, 
and  to  a  certain  degree  in  lean  meat,  potatoes,  yeast,  and 
wheat  bran.  Beef  suet  and  arachis  oil  also  contain  it  in 
small  amount,  and  have  recently  been  recommended  as  con- 
stituents of  artificial  cream,  for  feeding  infants  when  the 
natural  article  is  unobtainable. 

The  third  of  the  vitamines  at  present  recognised  possesses 
anti-scorbutic  activity,  and  is  known  as  Antiscorbutic  ;  it 
prevents  the  onset  of  scurvy.  It  is  present  in  fresh  vegetable 
foodstuffs  and  fruit  juice  —  lime  juice  particularly  may  be 
mentioned.  This  antiscorbutic  vitamine  is  less  stable  than 
the  others  ;  it  is  rapidly  decomposed  when  the  foodstuffs  in 
which  it  is  contained  are  heated,  and  even  when  they  are  kept 
too  long.  The  Water-soluble  B  or  anti-neuritic,  and  the 
Fat-soluble  A,  or  anti-rachitic,  vitamines  are  apparently 
permanently  stable  at  atmospheric  temperature,  and  are 
only  slowly  destroyed  by  heating  at  100°.  As  to  the  chemical 
nature  of  the  vitamines,  nothing  is  known  with  certainty. 
Drummond  and  Funk,  in  an  examination  of  the  phospho- 
tungstate  precipitate  containing  the  anti-neuritic  vitamine, 
found  it  to  contain  choline  and  nicotinic  acid  in  considerable 
amount.  This  led  Williams  to  test  the  curative  action  of 
certain  pyridine  derivatives  on  polyneuritic  pigeons.  He 
found  2-hydroxy-pyridine,  2.4.6,  and  2.3.4  trihydroxy 
pyridines  to  be  definitely  curative.  2-hydroxy-pyridine 
was  obtained  in  two  tautomeric  forms,  to  which  the  follow- 


ing  formulae  were  ascribed  ||     UTT  and  I     |!o 

\/u±1         \/ 
N  NH 

One  only  of  these  (the  latter)  is  anti-neuritic.  The  corre- 
sponding forms  of  3-hydroxy-pyridine  and  the  anhydrous 
forms  of  metbyl-pyridone,  trigonelline,  and  betaine,  were. 


3io          ORGANIC  MEDICINAL   CHEMICALS 

found  also  to  possess  curative  effects  on  polyneuritic  birds. 
Similarly,  nicotinic  acid  was  obtained  in  a  tautomeric  form 

with   a  betaine   structure    f|    |C^  and  this,  too,  was  anti- 

\£    I 
HN-0 

neuritic.  Williams  expresses  the  opinion  that  the  curative 
properties  of  the  vitamine  fractions  of  yeast  and  rice  polish- 
ings  are  due  in  part  to  the  presence  of  this  isomeric  form  of 
nicotinic  acid,  or  a  polymeride  or  simple  derivative  of  it. 
Further  work  on  these  lines  is  awaited  with  interest. 

Water-soluble  B  vitamine  extract  is  made  by  extracting 
rice  polishings  with  hot  alcohol  (90  %),  concentrating  under 
reduced  pressure,  treating  the  residue  with  water,  removing 
the  separated  fat,  and  adjusting  the  aqueous  portion  to  a 
finite  strength.  Stanton  (private  communication)  macerates 
the  polishings  with  cold  10  %  alcohol  which  has  been  acidified 
with  hydrochloric  acid,  filters,  and  concentrates  the  extract 
under  reduced  pressure,  at  as  low  a  teimperature  as  possible. 
The  extract,  to  which  is  added  10  %  of  alcohol  as  a  pre- 
servative, is  adjusted  so  that  one  part  by  volume  equals 
two  parts  of  rice  polishings. 

Preparations  which  are  freer  from  inactive  extractive 
matter  can  be  obtained  (see  U.  S.  P.  1235198)  by  extracting 
a  suitable  organic  foodstuff  with  dilute  alcohol,  and  removing 
the  alcohol  by  distillation  under  reduced  pressure.  The 
aqueous  solution  is  treated  with  lead  acetate  and  basic 
lead  acetate,  filtered,  the  filtrate  freed  from  lead  and  evapo- 
rated in  vacua  to  dryness.  Further  purification  may  be 
effected  by  precipitating  the  vitamine  with  either  tannin, 
silver  nitrate,  phospho-molybdic,  or  phosphotungstic  acids, 
and  decomposing  the  precipitates  by  appropriate  means. 

Williams  (Phillipine  J.  Sci.  (1916),  II,  49)  mixes  the  air- 
dried  phosphotungstic  acid  precipitate  with  excess  of  baryta, 
and  extracts  with  water.  The  extract  is  freed  from  barium 
and  sulphuric  acid,  neutralised  with  nitric  acid,  concentrated 
under  reduced  pressure,  and  then  treated  with  silver  nitrate. 
The  precipitated  purine  bases  are  separated  and  a  further 
quantity  of  .silver  nitrate,  and  sufficient  barium  hydroxide 


OTHER  SUBSTANCES  OF  INTEREST   311 

to  produce  a  permanent  precipitate,  added  to  the  solution. 
The  precipitate  is  decomposed  with  hydrogen  sulphide  and 
filtered,  barium  is  removed  as  sulphate,  and  the  solution 
then  concentrated  and  treated  with  twice  its  volume  of 
alcohol.  A  precipitate  forms  which  has  but  slight  anti- 
neuritic  properties.  The  filtrate  from  this  yields  on  evapo- 
ration a  substance  with  highly  curative  powers. 

Vitamine  from  brewers'  yeast  is  prepared  (U.  S.  P. 
1173317)  by  digesting  washed  and  pressed  brewers'  yeast 
for  36  hours  at  37*5°.  The  mass  is  filtered,  and  the  filtrate 
treated  with  about  50  grams  per  litre  of  Fuller's  earth.  The 
mixture  is  shaken  and  treated  with  about  I  %  of  N/i  hydro- 
chloric acid,  to  assist  settling.  The  sediment  is  filtered, 
washed  with  dilute  acid,  and  dried  in  vacua  over  sulphuric 
acid.  The  vitamines  contained  in  the  yeast  extract  are 
almost  completely  absorbed  by  the  Fuller's  earth.  The 
product  is  administered  without  further  treatment. 

SACCHARIN  (gluside,  o-benzoyl-sulphonimide) 

/\/CO\ 

( Y        )NH.     183. 

VNSQ/ 

The  preparation  of  saccharin  by  the  method  technically 
employed  can  be  resolved  into  three  stages. 

(1)  Preparation  and  purification  of  toluene-ortho-sulphon- 
chloride. 

(2)  Preparation    and  purification   of   toluene-ortho-sul- 
phonamide. 

(3)  Oxidation  of  ortho-toluene-sulphonamide  to  saccharin, 
These  will  be  considered  in  some  detail,  and  following  this 

will  be  given  a  resume  of  other  processes  for  obtaining 
saccharin  which  have  been  proposed. 

Preparation  of  Toluene -ortho -sulphonchloride. — 
(a)  By  the  sulphonation  of  toluene  with  sulphuric  acid : 
The  original  patentees,  Fahlberg  and  I,ist,  give  the  following 
description  of  the  method  employed  for  sulphonating 
toluene  (B.  P.  6626  of  1885) :— "  Toluene  may  be  treated 
with  fuming  sulphuric  acid  in  the  cold  state  or  it  is  heated 


312         ORGANIC  MEDICINAL  CHEMICALS 

with  hydrated  sulphuric  acid  of  66°  Be.  to  a  temperature  not 
rising  above  the  boiling  point  of  water.  In  applying  hydrated 
sulphuric  acid  the  reaction  takes  place  more  smoothly  than 
with  fuming  acid  and  without  any  boiling  over." 

A  quantitative  study  of  the  sulphonation  of  toluene  with 
sulphuric  acid  made  by  Holleman  and  Caland  (Ber.  (1911), 
44,  2504),  showed  that  the  higher  the  temperature  the  smaller 
is  the  proportion  of  toluene-ortho-sulphonic  acid  in  the 
mixture  of  isomerides  that  is  formed.  It  was  found  best 
to  sulphonate  at  o°,  and  most  economical  to  employ  two 
parts  by  weight  of  sulphuric  acid  (96-100  %)  to  each  part 
of  toluene.  Under  these  conditions  the  sulphonation  mixture 
contains  39*5  to  40  %  of  ortho-,  3*5  to  4*0  %  of  meta-,  and 
56  to  57  %  of  para-toluene-sulphonic  acids.  By  employing 
6  parts  of  sulphuric  acid  the  proportion  of  ortho-acid  is 
increased  to  45  %,  and  with  a  large  excess,  i.e.,  41*5  parts 
of  94  %H2S04,  to5i«5  %. 

The  components  are  mixed  in  a  cast-iron  vessel  provided 
with  a  powerful  stirrer  and  cooling  coils,  or  in  a  horizontal 
jacketed  autoclave,  maintained  at  o°,  and  stirred  until  a 
test-portion  dissolves  completely  in  water.  The  velocity 
of  sulphonation  would  probably  be  accelerated  by  adding 
infusorial  earth  until  the  mass  is  pasty  (D.  R.  P.  71556),  or 
powdered  animal  charcoal  (D.  R.  P.  74639),  whereby  the 
incorporation  of  the  hydrocarbon  with  the  acid  is  greatly 
facilitated.  The  sulphonation  mixture  is  run  into  cold  water, 
contained  in  a  wooden  vat,  and  is  neutralised  with  milk  of 
lime.  After  filtering  off  the  calcium  sulphate  the  sodium 
salt  is  prepared  by  treating  the  solution  with  sodium  car- 
bonate, separating  the  calcium  carbonate,  and  evaporating 
to  dryness. 

Several  methods  have  been  proposed  for  the  separation 
of  the  isomeric  acids  formed.  In  E.  P.  10955/1895,  this 
is  effected  by  crystallisation  of  the  magnesium  salts,  when 
magnesium  toluene-para-sulphonate  separates  first.  The  zinc 
salts  have  also  been  employed  (E.  P.  17,401/1896).  In  E.  P. 
15778/1890  the  sulphonation  mixture  is  diluted  with  ice 
until  the  concentration  of  the  sulphuric  acid,  6  parts  of 


OTHER  SUBSTANCES  OF  INTEREST   313 

which  are  employed  to  i  of  toluene,  is  66  %  w/w.  The 
para-  acid  is  only  sparingly  soluble  in  acid  of  this  strength, 
and  crystallises  out.  According  to  B.  P.  16299/1903,  400 
parts  of  toluene  are  sulphonated  at  i6°-i7°  with  1435  parts 
of  sulphuric  acid,  the  operation  being  completed  in  10  hours. 
Three  hundred  parts  of  water  are  added,  when,  on  standing, 
675  parts  of  para-acid  crystallise  out.  This  is  separated, 
and  a  further  80  parts  of  water  are  added  to  the  filtrate. 
The  ortho-acid  then  crystallises  out,  390  parts  being  obtained. 

Economy  is  effected  by  separating  the  isomers,  when 
employing  this  method  of  sulphonation,  as  thereby  phos- 
phorus pentachloride  is  saved  in  the  following  stage,  namely, 
that  of  chlorinating  the  para  compound.  The  toluene  con- 
tained in  the  acid  filtrate  from  the  ortho-acid  in  B.  P. 
16299/1903  can  be  regenerated  by  heating  to  160°  and 
blowing  in  superheated  steam,  when  the  sulphonic  acid 
is  decomposed.  The  separated  toluene-par a-sulphonic  acid 
is  resolved  into  toluene  and  sulphuric  acid  by  the  same 
means. 

Toluene-sulphonchloride : — Fahlberg  and  lyist  (loc.  cit.) 
prepared  the  sulphonchloride  by  mixing  the  dried  sodium 
salts,  in  a  lead-lined  iron  vessel,  with  phosphorus  penta- 
chloride, or,  preferably,  with  phosphorus  trichloride  followed 
by  treatment  with  chlorine.  The  temperature  is  regulated 
by  cooling.  Phosphorus  oxychloride  is  then  removed  by 
distillation,  after  which  the  sulphonchloride  is  allowed  to 
cool.  Crystals  of  the  para-chloride  separate  out  and  are 
removed  by  filtration.  The  liquid  filtrate  is  then  cooled 
to  o°,  when  a  further  crop  of  para-chloride  separates  and  is 
removed. 

Holleman  and  Caland  (loc.  cit.)  mixed  the  dried  sodium 
toluene-sulphonates  with  a  two-thirds  weight  of  phosphorus 
pentachloride  and  a  one-fifth  weight  of  phosphorus  oxy- 
chloride. The  reaction  was  completed  by  heating  to  I30°-i40° 
for  }  hour,  after  which  the  POC13  was  distilled  off  and  the 
residue  added  slowly  to  a  large  quantity  of  ice. 

In  B.  P.  11078/1898  a  variation  is  described  whereby 
sodium  toluene- ortho-sulphonate,  39  kilos,  is  mixed  with 


314         ORGANIC  MEDICINAL  CHEMICALS 

50  kilos  of  carbon  bisulphide  and  3  kilos  of  phosphorus, 
and  chlorine,  18  kilos,  passed  in  to  saturation. 


The  solvent  is  then  distilled  off  and  the  residue  of  toluene- 
sulphonchloride  converted  into  amide  by  treatment  with 
aqueous  ammonia.  Magnesium  toluene-ortho-sulphonate, 
250  kilos  (see  above),  is  converted  into  toluene-sulphon- 
chloride  (E.  P.  14390/1901)  by  slowly  adding  it  to  1250 
kilos  of  chlorsulphonic  acid,  the  temperature  being  main- 
tained at  i5°-i8°.  After  standing  for  a  few  hours  the 
mixture  is  poured  on  to  1000  kilos  of  ice  and  the  ortho- 
toluene-sulphonchloride  separated. 

(b)  By  sulphonation  with  chlorsulphonic  acid  :  —  Sulphuric 
acid  for  the  sulphonation  of  toluene  has  been  completely 
superseded  by  chlorsulphonic  acid,  whereby  the  ortho-  and 
para-toluene-sulphonchlorides  are  obtained  in  one  operation. 


C6H5CH3+2S02-OH.C1    -» 

92  2(116-4)  190-4         36-4        98 

This  great  improvement  was  introduced  by  Monnet 
(E.  P.  25273/1894).  Into  400  kilos  of  chlor-sulphonic 
acid,  cooled  to  o°,  there  are  run  slowly,  with  constant 
stirring,  100  kilos  of  toluene,  the  temperature  of  the  mass 
being  never  allowed  to  rise  above  5°.  When  all  the 
toluene  has  been  added,  the  mixture  is  constantly  stirred 
for  12  hours  in  order  to  complete  the  reaction,  the  temperature 
being  maintained  between  "o°  and  5°.  The  mass  is  then 
poured  on  to  ice,  when  the  sulphonchlorides  separate  in  the 
form  of  a  liquid  oily  layer  containing  some  solidified  para- 
chloride.  They  are  separated  by  decanting  off  the  upper 
aqueous  layer. 

The  sulphonation  is  carried  out  in  a  cast-iron  vessel, 
provided  with  a  powerful  stirrer  and  a  cooling  jacket 
through  which  circulates  cold  brine.  The  vessel,  which 
must  be  a  closed  one,  requires  an  inlet  tube  for  the  admission 
of  the  toluene,  and  an  exit  pipe  through  which  the  hydrogen 


OTHER  SUBSTANCES  OF  INTEREST       315 

chloride  vapour  is  led  away,  either  to  an  absorption  tower 
or  to  a  chlorsulphonic  acid  plant,  in  which  it  is  re-combined 
with  sulphuric  anhydride.  The  proportion  of  chlorsulphonic 
acid  to  toluene  may  advantageously  be  increased  to  5:1. 
The  greater  excess  of  acid  results  in  a  higher  yield  of  sulphon- 
chlorides,  and  the  choice  of  the  most  economical  proportions 
must  be  governed  by  the  respective  costs  of  the  ingredients. 
An  improvement  in  the  after-treatment  of  the  sulphona- 
tion  mixture  is  made  (D.  R.  P.  224386)  by  diluting  with 
saturated  hydrochloric  acid  until  the  sulphuric  acid  mixture 
has  a  specific  gravity  of  about  50°  Be.  At  this  concentra- 
tion the  sulphonchlorides  are  comparatively  insoluble  and 
separate  as  a  layer  on  the  surface  of  the  acid.  The  tempera- 
ture must  be  kept  down  as  near  as  possible  to  5°.  The 
hydrogen  chloride  liberated  from  the  hydrochloric  acid 
solution  and  that  formed  by  the  decomposition  of  the  excess 
of  chlorsulphonic  acid  is  absorbed  in  a  tower.  A  consider- 
able quantity  of  HC1  is  saved  by  this  procedure,  and  a 
stronger  residual  sulphuric  acid  results.  From  this  acid 
toluene  held  in  the  form  of  sulphonic  acid  can  be  regenerated 
(see  above). 

The  mixture  of  the  ortho-  and  para-toluene-sulphon- 
chlondes,  which  contains  doubtless  also  a  small  proportion 
of  meta-chloride,  is  partially  separated  by  freezing  out. 
Holleman  and  Calland  (loc.  cit.)  have  shown  the  melting 
point  of  pure  ortho-chloride  to  be  +10°,  that  of  pure  para- 
chloride  +67°,  and  that  a  eutectic  mixture  of  the  two  is 
formed  which  melts  at  +3 '5°,  and  has  the  composition 
ortho-  87*5  %,  para-  12*5  %.  '  In  practice  it  is  possible 
to  obtain  by  freezing  an  oil  containing  85  %  of  toluene- 
ortho-sulphonchloride. 

From  100  parts  of  toluene  about  no  parts  of  ortho- 
chloride  (85  %)  are  obtainable,  together  with  70-75  parts 
of  para-chloride. 

Preparation  of  Toluene-ortho-sulphonamide. — For 
the  conversion  of  toluene-ortho-sulphonchloride  into  the 
amide,  ammonia  gas,  ammonia  solution,  and  ammonium 
carbonate  have  been  employed. 


316          ORGANIC  MEDICINAL   CHEMICALS 

\S02C1+2NH4°H  -»  C6H4<CH3N 
190-4          70  171          53-4        36 


Fahlberg  and  lyist  (loc.  cit.)  recommended  ammonium 
carbonate.  The  sulphon-chloride  is  mixed  with  the 
theoretically  required  proportion  of  ammonium  carbonate 
and  the  pasty  mass  subjected  to  the  action  of  steam.  The 
resulting  product  is  treated  with  water,  whereby  the 
ammonium  chloride  is  dissolved  out,  the  residual  solid  being 
the  sulphonamide. 

An  alternative  method,  based  on  E.  P.  3930  of  1895, 
consists  of  adding  toluene-sulphonchloride  gradually  to 
an  equal  quantity  of  20  %  ammonia,  which  is  cooled  by 
being  surrounded  with  ice,  or  by  brine  coils.  The  reaction 
is  completed  by  warming,  after  which  the  toluene-sulphon- 
amide  is  filtered  off  and  washed  with  water. 

Purification  of  Toluene-ortho-sulphonamide.  —  The 
crude  product,  as  made  from  a  properly  frozen-out  oil, 
contains  not  less  than  85  %  of  ortho-amide  nor  more  than 
15  %  of  para-amide.  It  has  been  shown  by  McKie  (Trans. 
C.  S.  (1818),  799),  that  the  two  amides  form  a  eutectic  mixture 
having  the  composition  60  %  para-  and  40  %  ortho-amide. 
One  hundred  parts  of  the  crude  amide  containing  15  % 
of  para-,  therefore,  can  theoretically  be  separated  into  75 
parts  of  100  %  ortho-amide  and  25  parts  of  eutectic  mixture 
containing  60  %  of  para-  amide.  It  is  dissolved  in  the 
theoretically  required  quantity  of  normal  caustic  soda 
solution,  filtered  from  impurity,  and  treated,  whilst  being 
stirred,  with  acid  sufficient  to  precipitate  75  %  of  the  amide 
in  solution  (see  E.  P.  22726  of  1894).  Stirring  is  continued 
for  some  time  in  order  to  promote  the  attainment  of  equili- 
brium, or  the  solution  is  heated,  when  most  of  the  precipitated 
amide  passes  into  solution,  from  which  it  crystallises  again 


OTHER  SUBSTANCES   OF  INTEREST       317 

on  cooling.     The  product  is  a  nearly  pure  toluene-ortho- 
sulphonamide. 

In  place  of  acid,  ammonium  chloride  may  be  added, 
when  amide  is  precipitated  with  liberation  of  ammonia 
(B.  P.  848  of  1903), 


This  permits  of  the  employment  of  the  filtrate  containing 
ammonium  chloride  obtained  from  the  manufacture  of  the 
crude  toluene-sulphonamide. 

According  to  B.  P.  6198/1894  the  separation  of  the 
toluene-ortho-sulphonamide  can  be  brought  about  by 
crystallisation  of  the  sodium  salts  ;  or  by  following  B.  P. 
848/1903,  by  fractional  precipitation  with  a  magnesium 
salt,  when  the  magnesium  toluene-ortho-sulphonamide  is 
precipitated  first.  The  eutectic  mixture  of  amides,  obtained 
by  neutralisation  of  the  liquors  from  which  the  ortho- 
amide  has  been  filtered,  can  be  treated  (D.  R.  P.  133919) 
with  chlorsulphonic  acid,  when  the  toluene-sulphonchlorides 
are  reformed.  The  bulk  of  the  para-chloride  is  then 
removed  by  freezing,  and  the  ortho-chloride  reconverted 
into  amide. 

Another  method  of  partially  separating  these  amides 
consists  in  fractionally  crystallising  the  sodium  salts  from 
water,  when  much  of  the  para-  salt  separates  first,  allowing 
a  further  quantity  of  ortho-amide  to  be  precipitated  from 
the  filtrate.  The  amide  as  thus  obtained  contains  90-95  % 
of  ortho-amide  and  5-10  %  of  para-amide. 

Oxidation  of  Toluene-ortho-sulphonamide,  —  The 
oxidation  of  the  ortho-amide  to  saccharin  is  usually  carried 
out  by  means  of  potassium  or  sodium  permanganate,  though 
calcium  and  ammonium  permanganate  have  also  been 
recommended.  Varied  and  conflicting  statements  as  to 
the  conditions  under  which  the  oxidation  is  best  carried 
out  are  to  be  found  in  the  patent  literature,  and  careful 


318         ORGANIC  MEDICINAL  CHEMICALS 

sifting  of  the  evidence  is  required  in  order  to  arrive  at  a 
procedure  likely  to  be  productive  of  good  results. 

Fahlberg  and  lyist  give  no  particulars  whatever  as  to 
temperature,  concentration,  quantity  of  permanganate 
employed.  The  following  equation  represents  the  reaction, 
in  their  view  : — 


171  3*6 

->    C6H4^Q2))NK+KOH+2MnO2+2H2O 
221 

They  say  it  is  necessary  to  neutralise,  during  the  progress 
of  the  reaction,  the  alkali  that  is  formed.  In  Ber.  21,  243, 
they  state  that  in  acid  solutions  ortho-sulphobenzoic  acid 
is  formed  ;  in  neutral  solutions  saccharin  together  with 
ortho-sulphobenzoic  acid  ;  and  in  alkaline  solutions  ortho- 
sulphamino-benzoic  acid.  Hauff,  in  E.  P.  3680  of  1898, 
states  that  if  the  oxidation  is  carried  out  according  to 
Fahlberg's  method  and  neutralising  agents  are  added,  no 
saccharin  is  obtained ;  but  that  if,  on  the  contrary,  the 
sulphonamide  be  dissolved  in  alkali,  to  form  the  compound 


>  and  oxidised  with  permanganate  without 

the  addition  of  neutralising  agents,  larger  yields  (80-90  %) 
of  saccharin  are  afforded. 

Theoretically,  1*89  parts  of  potassium  permanganate 
are  required  to  oxidise  i  part  of  toluene-sulphonamide  to 
saccharin.  Hauff  employed  2*57  parts,  and  in  E.  P.  4525/1900 
2'5  parts  are  given.  In  E.  P.  3563/1903,  however,  it  is 
stated  that  better  results  are  obtained  by  using  permanga- 
nate insufficient  to  oxidise  the  whole  of  the  amide,  and 
i -5  parts  are  used,  part  of  the  amide  being  recovered 
unchanged. 

E.  P.  4525/1900  is  specific  on  the  points  of  temperature 
and  dilution.  It  is  stated  that,  using  a  concentration  of  i 
of  amide  in  15,  the  temperature  should  be  kept  between  40° 


OTHER  SUBSTANCES   OF  INTEREST       319 

and  50°,  whilst  at  a  dilution  of  i  in  60  a  temperature  of 
9°°-95°  is  desirable.  Solid  permanganate  is  employed 
according  to  this  patent. 

High  dilutions  are  disadvantageous  on  account  of  the  loss 
of  saccharin  by  reason  of  its  solubility. 

The  best  conditions  based  upon  the  above  published 
accounts  are  as  follows  :  One  molecular  equivalent  of  toluene 
sulphonamide,  171  parts,  is  dissolved  in  i  equivalent  of 
caustic  soda,  40  parts,  and  2565  parts  of  water,  contained 
in  a  lead-lined  vessel.  At  a  temperature  of  40°-50°  are 
added,  with  stirring,  and  in  small  quantities  at  a  time,  256 
parts  of  potassium  permanganate.  The  addition  of  the 
permanganate  is  spread  out  over  the  whole  period  of  the 
oxidation.  When  completed,  and  when  the  colour  of  the 
permanganate  has  nearly  disappeared,  the  excess  is  destroyed 
by  addition  of  sodium  hydrogen  sulphide  and  the  solution 
filtered  from  the  precipitated  manganese  compound,  which 
is  washed  with  water  until  addition  of  acid  to  the  filtrate  no 
longer  produces  a  precipitate  of  saccharin. 

The  combined  filtrate  and  washings  is  cooled  to  i5°-i8D 
and  made  neutral,  to  methyl  orange,  with  hydrochloric  acid. 
The  excess  of  toluene-sulphonamide  is  thereby  precipitated, 
and  is  filtered  off.  The  filtrate  is  treated  with  hydrochloric 
acid  exactly  equivalent  to  the  amount  of  para-amide  present 
in  the  amide  taken  for  oxidation  (B.  P.  1164  of  1897).  In 
place  of  hydrochloric  (or  sulphuric)  acid  saccharin  itself  may 
be  used  (B.  P.  22787/1891).  By  this  treatment  the  para- 
sulphonamido-benzoic  acid  which  has  been  formed  by  oxida- 
tion of  the  para-amide,  being  a  much  weaker  acid  than 
saccharin,  is  precipitated.  From  the  filtrate,  saccharin  is 
precipitated  by  addition  of  a  further  quantity  of  hydrochloric 
acid  and  is  filtered  off,  washed  with  cold  water  and  dried 
at  a  moderate  temperature  (35°-40°).  A  further  small 
quantity  can  be  obtained  by  saturating  the  filtrate  with  salt. 

Electrolytic  Oxidation  of  Toluene-sulphonamide.  — 
In  B.  P.  8661/1895  the  oxidation  of  toluene-sulphonamide 
by  passing  a  current  of  electricity  through  its  solution,  in 
an  alkali,  is  proposed. 


320         ORGANIC  MEDICINAL  CHEMICALS 


A  more  promising  method  is  described  (E.  P.  9322/1803), 
in  which  potassium  permanganate  is  employed  as  a  carrier 

of  the  electrolytic  oxygen. 

A  is  a  vat  furnished 
with  a  lining  of  lead,  tin, 
or  other  conducting  sub- 
stance (D)  not  capable  of 
affecting  the  reagents.  This 
lining  forms  the  cathode. 
Inside  the  vat  is  a  vessel  B 
of  porous  porcelain  in  which 
is  suspended  a  lead,  or  lead- 
coated  iron,  sheet  C,  which  constitutes  the  anode,  and  is 
fixed  to  the  shaft  of  an  agitator. 

According  to  the  conditions  given,  0*9  kilo  of  potassium 
permanganate  is  dissolved  in  13  litres  of  10  %  sodium 
hydroxide  solution,  or  in  potassium  hydrate  or  baryta,  and 
the  volume  made  to  40  litres  with  water.  Another  solution 
is  prepared  containing  2  kilos  of  ortho-amide  and  500  grams 
of  caustic  soda  in  12  litres  of  water. 

The  permanganate  solution  is  placed  in  B,  4  litres  of 
the  amide  solution  are  added,  and  the  whole  is  heated  to 
40°-5o°,  when  a  current  of  300  amps,  at  below  2  volts  is 
passed  through  it.  After  2  hours,  1800  c.c.  of  the  amide 
solution  are  added,  and  this  addition  is  renewed  every  hour. 
The  temperature  is  maintained  for  an  hour  after  the  last 
addition,  after  which  the  current  is  arrested,  the  perman- 
ganate destroyed,  and  the  saccharin  isolated  in  the  usual 
manner. 

It  will  be  noted  that  this  oxidation  was  carried  out  in 
the  presence  of  a  large  excess  of  caustic  alkali,  which  Fahlberg 
and  others  have  shown  to  be  conducive  to  the  formation  of 
sulphamido-benzoic  acid  at  the  expense  of  the  saccharin, 
and  that  a  small  yield  only  of  the  latter  is  to  be  expected. 
Probably,  however,  by  observance  of  the  conditions 
set  out  in  connection  with  the  oxidation  by  means  of  per- 
manganate, an  electrolytic  oxidation,  with  the  aid  of  a  carrier 
such  as  permanganate,  could  be  successfully  carried  out. 


OTHER  SUBSTANCES   OF  INTEREST       321 

Other  Methods  of  Synthesis  of  Saccharin.  —  Brief 
reference  is  given  only  to  the  more  important  of  the  other 
methods  that  have  been  proposed  for  obtaining  saccharin. 
None  of  them  has  competed  commercially  with  the  toluene- 
chlorsulphonic  acid  process. 

i.  Fahlberg  (B.  P.  10955/1895)  :— 

H3  /NCOOH  /VOOR 

S 

OR 


S02C1  02NH2 

2.  Easier  (D.  R.  P.  80713/1893)  :— 

/scoa       /NcoNH2 

(JSBL      -*  1 


3.  Cerckel    (B.    P.    15493/1896)  :     Ortho-cresol,    heated 
under  pressure  with  ammonium  thiocyanate,  gives  toluene- 
ortho-sulphonamide . 

4.  A  number  of  patents  deal  with  the  preparation  of 
toluene-ortho-sulphinic     acid,    and     its     conversion     into 
saccharin . 

B.  PP.  26139/1896 ;  23047/1897 ;  12871/1900 ; 
7288/1906  ;  13054/1906  ;  13055/1906,  deal  with  the  following 
reactions  : 

CH3 
NH2 

/NCHg  /NCHs        toluene- ortho- 

~>     ks/JN=NSO3H     "^     ly^SOgH      sulphinic  acid. 

Ortho-toluene-sulphinic  acid  is  converted  into  toluene-o- 
sulphonchloride  (B.  PP.  4525/1900  ;  10356/1906)  or  directly 
into  toluene-o-sulphonamide  (B.  P.  12585/1900). 

5.  I/astly  may  be  mentioned  the  conversion  of  ortho- 
sulphonamido-benzoic  acid,  which  is  formed  to  a  varying 
extent  as  a  by-product  during  the  oxidation,  and  which  can 
be  obtained  in  quantitative  yield  by  oxidising  in  a  strongly 
alkaline  solution,  into  saccharin.     By  B.  P.  1164/1897,  10 

I.  21 


322          ORGANIC  MEDICINAL  CHEMICALS 

kilos  of  0-sulphamido- benzole  acid  are  dissolved  in  40  kilos  of 
98  %  alcohol,  2  kilos  of  concentrated  sulphuric  acid  are 
added,  and  the  mixture  boiled  under  a  reflux  condenser  for 
several  hours.  The  alcohol  is  then  distilled  off  and  the  residue 
poured  into  cold  water,  when  ethyl-ortho-sulphamido- 
benzoate  separates  as  an  oil  which  quickly  solidifies.  The 
ester  is  then  heated  at  ioo°-iio°  with  constant  stirring, 
ethyl  alcohol  is  split  off,  with  the  formation  of  saccharin. 

By  another  method,  B.  P.  19629/1899,  40  kilos  of  ortho- 
sulphamido-benzoic  acid  are  introduced  slowly,  with  good 
stirring,  into  120  kilos  of  20  %  fuming  sulphuric  acid,  care 
being  taken  that  the  temperature  does  not  rise  above  40°. 
The  clear  solution  is  allowed  to  stand,  at  ordinary  temper- 
ature, for  24  hours,  after  which  it  is  poured  upon  a  mixture 
of  300  kilos  of  ice  and  100  kilos  of  water.  Saccharin  is 
precipitated,  and  filtered  off.  Yield,  95  %. 

According  to  E.  P.  7199/1900  the  ortho-sulphonamido- 
benzoic  acid  is  heated  in  alcoholic  solution  with  dry  powdered 
sodium  acid  sulphate,  or  sodium  pyro-sulphate.  A  mixture 
of  saccharin  and  its  ester  is  said  to  be  formed,  which,  on 
solution  in  caustic  soda  and  acidification  with  acid,  affords 
a  yield  of  over  95  %  of  saccharin. 

Saccharin  is  a  white  crystalline  powder,  possessing  an 
extremely  sweet  taste.  It  dissolves  in  400  parts  of  cold 
water,  in  28  parts  of  boiling  water,  and  in  38  parts  of  alcohol. 
It  is  readily  soluble  in  alkalis  or  alkali  carbonates,  with 
formation  of  salts.  M.p.  220°. 

Saccharin  should  contain  not  less  than  97  %  of  o-benzoyl- 
sulphonimide  (for  method  of  estimation  see  Richmond  and 
Hill,  /.  S.  C.  I.  (1918),  37,  246  T).  It  should  form  a  clear 
solution  when  treated  with  sodium  bicarbonate  and  water 
(absence  of  toluene-sulphonamide). 

No  carbonisable  impurities  should  be  present,  as  shown  by 
a  solution  of  0*2  gram  in  10  c.c.  of  pure  sulphuric  acid  warmed 
at  50°  not  showing  a  brown  colour  in  10  minutes. 

Ammonium  salts  should  be  absent,  and  no  weighable 
residue  should  be  left  after  ignition  of  0*5  gram. 

Saccharin    should    form    a    clear    solution    in    aeceton. 


OTHER   SUBSTANCES   OF  INTEREST       323 

Absence  of  ortho-sulphonamido-benzoic  acid  is  shown  by 
the  acidity  of  the  filtered  solution  obtained  after  shaking 
I  gram  of  saccharin  with  10  c.c.  of  water  for  i  hour  at  20 °, 
which  should  not  be  appreciably  greater  than  that  calculated 
for  a  0*3  %  solution  of  saccharin. 

Saccharin  is  used  as  a  substitute  for  sugar  and  is  prescribed 
in  cases  of  diabetes  and  hepatic  disease,  also  in  corpulence. 
It  is  also  employed  to  disguise  the  taste  of  nauseous 
drugs. 


INDEX 


£-ACETAMINOPHENOL,   119 

Acetanilide,  113,  114 
Acetone-ethyl-mercaptol,  33 
Acetophenone,  16,  254 
Acetphenetidine,  116 
Acetum  Scillce,  291 
Acetylsalicylic  acid,  140 
Acocanthera  Schimperi,  290 
Aconitine,  87 

hydrobromide,  87 
Aconitum  napellus,  87 

uncinatum,  87 
Acriflavine,  190 
Adalin,  40 

.Adrenaline,  211,  217 
Adrenine,  217 
Albumen  tannate,  193 
Alkylation,     reaction     vessel     for 

(diagram),  67 
Allosan,  196 
Ally!  iodide,  294 

isothiocyanate,  293 
Aloe-emodin,  198 
Aloes,  198 
Aloin,  198 
Alypine,  89,  90,  102 
Amino-antipyrine,  127 
^-Aminobenzoic  acid,  109 

ethyl  ester,  109,  110 
p-  Amino-benzoyl-chlorethanol,  104 

-benzoyl  -  diethyl  -   amino    - 

ethanol,  109 

4-/?-Amino-ethyl-glyoxaline,  215 
3-Amino-4-hydroxyphenyl-arsenic 

acid,  275 

^-Amino-methyl  salicylate,  110 
o-Aminophenol  hydrochloride,  192 
p- Amino  phenylarsinic  acid,  256 
^-Aminosalicy lie  acid,  112 

methyl  ester,  111 
Amyl  nitrite,  224 
Anaesthesine,  109 
-  Analgesin,  124 
Andira  araroba,  204 
Anhydroformaldehyde  aniline,  188 
Anisic  aldehyde,  215 


o-Anisidine,  158 
Anthrapurpurin,  197 
Antifebrin,  114 
Antipyrine,  113,  124 

salicylate,  126 
Antiscorbutic  vitamine,  309 
Apocynum  cannabinum,  283 
Apomorphine,  58 

hydrochloride,  58 

Aqueous  liquids,  extraction  of  (from 
light  solvents)  (diagram),  51 
Araroba,  204 
Argonin,  279 
Aristol,  179 
~  -  Arsanilic  acid,  256 
-  -  Arsenobillon,  259 
-  Arseno-phenyl-glycine,  258 
Arterenal,  222 
Articol,  195 
--Aspirin,  113,  140 
Atophan,  230,  253 
Atoxyl,  256 
Atropa  belladonna,  68 
Atropine,  68,  70 
sulphate,  69 

Autoclave,  high  pressure  (diagram), 
136 


BALL  MILL,  steam-heated  (diagram )j 

75 

Barbaloin,  198,  199 
Barbitone,  43 
Benzamine,  96 

hydrochloride,  99 
Benzene- w-disulphonic  acid,  154 
Benzenesulphonic  acid,  147,  153 
Benzoic  acid,  130 

sublimer  (diagram),  132 
Benzoyl-pseudo  tropine,  95 
o-Benzoyl-sulphonimide,  311,  322 
Benzoyl  -  tetramethyl  -  diamino  -  di  - 
methyl-carbinol,  103 

-vinyl-diacetonalkamine,  96 
Benzyl  cyanide,  215 
Benzyltetrahydroberberine,  64 


325 


326 


INDEX 


Berberine,  64 

acid  sulphate,  60 
Beri-beri,  307 
Betaine,  309 
Betula  lenta,  140 
Bismuth  tribromphenolate,  173 
Brassica  nigra,  293 
Bromaceto-pyrocatechol,  219 
Bromodiethylacetamide,  42,  43 
Bromodiethyl-acetyl  bromide,  41 

carbamic  chloride,  42 

cyanate,  43 

isourea  methyl  ether,  42 

-phenyl-carbamate,  42 

urea,  40,  42 

Bromodiethylcyanamide,  42 
Bromodiethyl  thiourea,  42* 
Bromol,  173 
Bromural,  47 
Brucine,  81 
Butyl  chloral  hydrate,  29 


CAFFEINE,  230 

Calcium  acetylsalicylate,  144 

glycerophosphate,  297 

iodo-behenolate,  181 
Camellia  Thea,  239 
Cantharidin,  292 
Cantharis  vesicatoria,  292 
Carbamic  chloride,  38 
Carbolic  acid,  147 
Carum  coplicum,  164 
Cascara,  liquid  extract  of,  201 

Sagrada,  200 

extract  of,  201 
Cephadine,  65,  66 
Chinosol,  192 

Chloraceto-pyrocatechol,  218 
Chloral  alcoholate,  27 
Chloralamide,  29 
Chloralformamide,  29 
Chloral  glucose,  28 

hydrate,  26 
Chloralose,  28 
Chloramine-T,  167 
8-Chlor-caffeine,  231 
Chloretone,  30 

Chlorinating  vessel  (sketch),  26 
Chloroform;  20 

manufacture      from      acetone 
(diagram),  24 

production  of  (diagram),  21 

purification,    washer   for    (dia- 
gram), 25 

4-Chlorophenyi-arsinic-acid,  264 
Chlortheobromine,  248 
Choline,  309 
Chrysarobin,  204 


Chrysophanic  acid,  197 
Cinchona  bark,  alkaloids  of,  74 

ledgeriana,  74 

succirubra,  74 
Cinchonidine,  74,  78 

hydrobromide,  79 

sulphate,  79 
Cinchonine,  74,  79 

sulphate,  79 

Citrullus  Colocynthis,  204 
Claviceps  purpurea,  212 
Cocaine,  89,  91 

crude,  91 

Java,  92 

hydrochloride,  92 
Coca  leaves,  Java,  95 

Peruvian,  95 
Cocoa  beans,  246 
Codeine,  53,  55 

hydrochloride,  58 

phosphate,  57 

sulphate,  58 
Colchicine,  86 

salicylate,  86 
Colchicum  autumnale,  86 
Colocynthin,  204 
Convallaria  majalis,  283 
Convolvulus  Scammonia,  207 
Cotarnine,  59 

hydrochloride,  60 

phthalate,  60 
Cytisus  scoparius,  84 


Datura  arbor ea,  71 

Fastuosa,  71 

metel,  71 

stramonium,  71 
Diacetonamine,  97 
Diacetyl-diamino-uracil,  231,  240 

-protocatechuic  aldehyde,  221 

nifigallic       acid       tetramethyl 
ester,  203 

-tannin,  194 

/>-£-Diaminodiphenyl-methane,   188 
2-6-Diamino  acridine,  188 

-acridinium        metho-chloride, 

190 
3:3'-  Diamino  -  4  :  4'  -  dihydroxy  - 

arsenobenzene,  259,  274 
Diazomethane,  56 
Dichloramine-T,  170 
^-Dichlorsulphonaminobenzoic  acid, 

171 

£-£-Diethoxy-azo-benzol,  116 
Diethylacetic  acid,  41 
Diethylacetyl  urea,  42 
Diethylamine,  107 

sulphonic  acid,  107 


INDEX 


327 


Diethylamino-ethanol,  104,  108 
Diethyl  barbituric  acid,  43 
Diethylbromoacetamide,  48 
Diethyl-cyanoacetic  ester,  44 
Diethylene-diamine,  249 
Diethyl    glycocoll-/?-amino-salicylic 

acid,  112 
Diethyl  glycocoll  ester,  111 

hydantoin,  42 

Diethylmalonic  ester,  41,  43 
Diethyl-malonyl  chloride,  44,  45 

-urea,  43 

-sulphone-dimethyl-methane,  32 
Digitalin  amorphous,  285 
Germanicum,  286 
Homolle,  285 
Nativelle,  284 
Verum,  286 
Digitalis,  infusion  of,  284 

tincture  of,  284 
Digitalis  purpurea,  284 
Digitoxin,  287 
4:4'-  Dihydroxy  -  arsenobenzene  - 

3  :  3'-phosphamic  acid,  275. 

276 

w-Dihydroxy-benzene,  153 
3 :  4-Dihydroxy-phenyl-ethyl- 

methylamine,  222 
2  :  4-Diimino-5-dialkyl  -  6  -  oxypyri- 

midine,  45 
Di-iodo-phenol-£-sulphonic        acid, 

178 

Di-iodo-thymol,  179 
Dimethyl-amino-acetone,  101 
Dimethyl  -  amino  -  dimethyl  -  ethyl- 

carbinol,  100 
1  :  3-Dimethyl-4-amino-2  :  6  -  dioxy 

pyrimidine,  232 
Dimethyl  -  amino  -  nitro  -  phenyl  - 

arsinic  acid,  266 
4  -  Dimethyl-amino-3-mtro-phenyl  - 

arsinic  acid,  265 
Dimethyl  -  amino  -  phenyl  -  arsinic 

acid,  265 
1:3-  Dimethyl  -7-  hydroxy-methy- 

ene  uric  acid,  231 
Dimethyl  sulphate,  56 
urea,  232,  236,  240 
uric  acid,  247 

1 :  3-Dimethyl-xanthine,  239 
Dinitroso-diphenyl-piperazine,  249 
Diphenyl-piperazine,  249 
Disodio  luargol,  275 
Duotal,  159 


ECGONINE  hydrochloride,  93 
Emetamine,  65 
Emetine,  65 


Emetine — 

hydrobromide,  66 

hydrochloride,  66 
Emodin,  197 

Enamelled  Still  (diagram),  152 
Epinephrine,  217 
Epinine,  222 
Ergot,  211 
Ergotinine,  214 
Ergotoxine,  212 

alkaloid,  213 

phosphate,  213 
Erythrol  tetranitrate,  227 
Erythroxylon  Coca,  91 

Spruceanum,  91 

Truxillense,  91 
Eseramine,  84 
Eserine,  84 

hydrobromide,  85 

salicylate,  85 

sulphate,  85 
Ether,  9 

production     and     rectification 
plant,  10 

purification,  rectifier  for  (illus- 
tration), 14 

£-Ethoxy-£-oxyazobenzol,  116 
ta  -  Ethylamino  -3:4-  dihydroxy  - 

acetophenone,  222 
Ethyl  bromide,  18 

carbamate,  37 

chloride,  17 

chloroformate,  160 

cyanoacetate,  236 
£-Ethyl  dichlorhydrin,  102 
Ethyl  diethylmalonate,  41 

malonate,  40 

mercaptan,  32 

nitrite,  223 

sulphonal,  35 
Eucaine,  90 
a-Eucaine,  89 
/J-Eucaine,  89,  96 

hydrochloride,  99 

lactate,  100 
Euresol,  156 
Exalgin,  115 
Exodin,  203 

Extraction     Plant — Fischer     type 
(illustration),  50 

FAT-SOLUBLE-A-VITAMINE,  309 
Film  evaporator  (diagram),  234 
Formaldehyde,  183 
/>-Formaldehyde,  187 
Formaldehyde      plant      (diagram), 

186 

Formalin,  183 
Formol,  183 


328 


INDEX 


Formyl  homopiperonylamine,  63 
Fractionating    column,    section    of 
(diagram),  11 

GALLIC  acid,  203 

Galyl,  270,  275 

Gaultheria  procumbens,  140 

Gitalin,  287 

Glonoin,  226 

Glucochloral,  28 

Gluside,  311 

Glycerine,  300 

Glycerophosphoric  acid,  preparation 

of,  299 
a-    and    /?-Glycerophosphoric    acid, 

297 
Glycol  bromacetate,  105 

bromhydrin,  104 

diacetate,  105 
Goa  powder,  204 
Guaiacol,  157 

carbonate,  159 

HALAZONE,  171 
Hedonal,  38 
Hexamine,  187 
Hexanitrin,  228 
Hexanitro-mannitol,  228 
Hexa-oxy-anthraquinone,  203 
High  pressure  autoclave  (diagram), 

136 

Histamine,  211,  215 
Histidine,  216 
Homatropine,  72 

hydrobromide,  730 
Homopiperonylamine,  63 
Homorenon,  222 
Horizontal    M.S.     steam- jacketed 

agitator  (diagram),  137 
Hydrastine,  60,  62 

acid  oxalate,  61 
„    tartrate,  61 

hydrochloride,  61 
Hydrastinine,  61 

hydrochloride,  65 
Hydrastis  Canadensis,  60 
Hydrocotarnine,  62 
Hydrohydrastinine,  62 
7-Hydroxy  methylene  uric  acid,  231 
p-Hydroxyphenyl-arsinic  acid,  261 

-ethylamine,  211,  214 
3-Hydroxy-pyridine,  309 
Hyoscine,  68,  71 

hydrobromide,  71 
Hyoscyamine,  68 
Hyoscyamus  muticus,  68 

niger,  71 
Hypnal,  126 
Hypnone,  16 


/MMINAZOLYL-ETHYLAMINE,       211, 

215 

lodipin,  177 
Iodised  sesame  oil,  177 
lodoform,  174 
lodol,  176 
lodo  -  8  -  oxyquinoline  -  5  -  sulphonic 

acid,  180 
I-pomcea  orizabensis,  207 

purga,  205 

Iron  glycerophosphate,  297 
Isatin,  254 
Isoamyl  nitrite,  224 
Iso-propyl-w-cresol,  164 


JALAP,  205 

extract  of,  206 
Jalapin,  206 
Jalap  Resin,  206 
Java  Coca  leaves,  95 


KHARSIVAN,  259 


LACTOPHENIN,  123 

Lactyl  phenetidine,  123 

Laevo-hyoscyamine  sulphate,  69 

Lead-coated  washer  (diagram),  76 

Lecithin,  294 

extraction  of,  from  seeds,  296 
preparation   of,   from   yolk   of 
egg,  294 

Liquor  jormaldehydi,  183 

Loretin,  180 

Luargol,  270,  274 
disodio,  275 


MAGNESIUM  glycerophosphate,  297 
Malachite  green,  191 
Malonic  ester,  40 
Mannitol  hexanitrate,  228 
Medinal,  45 

Mercury      di - iodo-  phenol -p-  sul- 
phonate,  179 

salicylate,  280 

sozoidol,  179 

siccinimide,  281 
Methanal,  183 
Methoxy-phenyl-propionic  acid,  215 

pyrocatechol,  157 
Methyl-acetanilide,  115 

-acetyl-urea,  246 
Methylal,  15 
Methyl  alcohol,  183 
Methylamino-acetocatechol,  219 


INDEX 


329 


Methyl  -  p  -  chloracetylamino  -  sali  - 
cylate,  112 

-ecgonine,  93 

vacuum  still  for  (diagram),  94 
Methylene-dioxy-nitrostyrol,  63 

ditannin,  194 
Methyl-isocyanate,  232 
Methylpropyl-carbinyl-urethane,  38 
Methyl-pyridone,  309 

salicylate,  140 
Methylsulphonal,  35 
Methyl  urea,  246 
8-Methyl-xanthine,  231,  233 
Monarda  punctata,  164 
Monoacetyl  resorcin,  156 
C-Monoalkylbarbituric  acid,  45 
a-Monobromoisovaleryl  urea,  47 
Monochloracetone,  101 
/3-Monohydroxy-naphthalene,  165 
Mono-iodo-behenolic  acid,  181 
Mono-methylaniline,  115 
Morphine,  52 

acetate,  54 

hydrochloride,  54 

sulphate,  54 

tartrate,  54 
Mosula  japonica,  164 
Mustard,  oil  of,  293 


5-NAPHTHOL,  165 

Narcotine,  53,  59,  62 
Neo-salvarsan,  270,  271 

silver,  274 
Neuronal,  48 
New  orthoform,  90 
Nicotinic  acid,  309 
Nirvanine,  90,  110 
o-Nitroanisol,  157 
p-Nitrobenzoyl-chlorethanol,  104 
chloride,  104,  108 
-diethylamino-ethanol,  104, 108 
Nitroglycerin,  226 
Nitro-hydroxyphenyl-arsinic     acid, 

266 
3  -  Nitro  -  4  -  hydroxyphenyl  -  arsinic 

acid,  electrolytic  reduction  of, 

268 

#-Nitro-£-methoxy-styrene,  215 
3-Nitro-4-oxyphenvl-arsinic       acid, 

266    ' 

o-Nitrophenol,  192 
£-Nitrophenol,  117 
Nitroso-antipyrine,  127 
Nitroso-methyl-urethane,  56 
^-Nitrosophenol,  121 
Nosophen,  182 
Novatophan,  255 
Novocaine,  90 


OIL  of  mustard,  293 

Organic  antimony  compounds,  277 

mercury  compounds,  279 
Ouabain,  290 
Oxanil-4- arsinic  acid,  263 
o-Oxyquinoline,  160,  192 

sulphate,  192 


PAPAVERINE,  53 
Papaver  sommferum,  52 
Paraldehyde,  15 
Paratophan,  255 
Peruvian  Coca,  95 
Phenacetin,  113,  116 
Phenazone,  124 
^-Phenetidine,  116,  118 
Phenol,  147 

Phenolphthalein,  197,  209 
Phenol-£-sulphonic  acid,  179 
Phenyl-ethylamine,  215 

-glycine-£-amino-phenyl-arsinic 

acid,  258 
2-Phenyl-4-quinoline-carboxylic 

acid,  253 

Phenyl  salicylate,  151 
Phthalic  anhydride,  209 
Physostigmine,  84 
Physovenine,  84 
Phytin,  297 
Picropodophyllin,  208 
Pilocarpine,  82 

hydrochloride,  83 

nitrate,  83 

Pilocarpus  jaborandi,  82-83 
Piperazine,  249 
Pituitary  gland,  230,  302 

extract  of,  303 
Podophyllin,  208 
Podophyllo-quercitin,  208 
Podophyllo-toxin,  208 
Podophyllum  emodi,  208 

peltatum,  208 

Potassium         di-iodo-phenol-£-sul« 
phonic  acid,  179 

glycerophosphate,  297 

guaiacol-sulphonate,  161 

isocyanate,  38 

thiocyanate,  294 
Proflavine,  188 
Protargol,  278 
Protein      compounds      containing 

silver,  278 
Pseudo  tropine,  95 
Psychotria  acuminata,  65 

Ipecacuanha,  65 
Psychotrine,  65 

O-methylether,  65 
Ptychotis  ajowan,  164 


330 


INDEX 


Purgen,  209 
Pyramidon,  126 


QUINIDINE,  79 
sulphate,  80 

Quinine,  74,  75 

bihydrochloride,  77 
bisulphate,  77 
hydrobromide,  77 
hydrochloride,  77 
phosphate,  77 
sulphate,  76 


RESORCINOL,  153 
Rheum  palmatum,  202 
Rhubarb,  202 

concentrated  solution  of,  202 

extract  of,  202 

infusion  of,  202 
Rhus  toxicodendron,  283 
Rufigallic  acid,  203 


SACCHARIN,  311 

methods  of  synthesis  of,  321 
Sajodin,  181 
Salicin,  113,  292 
Salicylic  acid,  133 
Salicylosalicylic  acid,  143 
Salipyrine,  126 
Salol,  151 
Salvarsan,  259,  266,  269 

silver,  273 

and  Neo-salvarsan,   co-ordina- 
tion compounds  of,  273 
Santalol,  195 

carbonate,  196 
Santalyl  allophanate,  198 

carbamate,  196 
Scammony  resin,  207 
Scilla  maritima,  291 
Scillitin,  291 
Scopolamine,  68,  71 
Scopolia  carniolica,  68 

japonica,  71 
Secale  cornutum,  212 
Senigrin,  293 
Senna,  204 
Silver  neo-salvarsan,  274 

salvarsan,  273 
Soamin,  256 
Sodium  acetylsalicylate,  145 

/>-amino-phenyl-arsenate,  257 

benzene-sulphonate,  148 

3  :  3'-diamino-4  :  4'-dihydroxy- 
arsenobenzene-N-methylene- 
sulphinate,  271 


Sodium  dihydrogen,  phosphate,  300 

di-iodo-phenol-/?-sulphonfcacid, 
179 

glycerophosphate,  297 

naphthalene-/?-sulphonate,  166 

salicylate,  139 

salvarsan,  271 

toluene  -p-  sulphonchloramine, 

167 

Sozoiodol,  178 
Sparteine,  84 

sulphate,  84 

Spiritus  A  etheris  Nitrosi,  223 
Squill,  291 

tincture,  of  291 

Stearyl-glycerophosphoric  acid,  294 
Stovaine,  89,  90,  100 
Strophanthin,  288,  289 
Strophanthus,  288,  290 

tincture  of,  288 

Grains,  289 

Hispidus,  289 

Kombe,  289 
Strychnine,  80 

hydrochloride,  81 

nitrate,  81 

sulphate,  81 
Strychnos  Ignatii,  80 

Nux-vomica,  80 

Tieute,  80 
Stypticine,  60 
Styptol,  60 
Sulphoform,  277 
Sulphonal,  32,  32 
/j-Sulphonamido-benzoic  acid,  319 
Sulphone  hypnotics,  31 
Suprarenal  glands,  217 
Suprarenin,  217 


TANNALBEN,  193 
Tannic  acid  derivatives,  193 
Tannigen,  194 
Tannocol,  194 
Tannoform,  194 
Tea  dust,  233 

Tetra-hydroxy-anthraquinone,  197 
-  hydroxy  -  methyl  -  anthraqui  - 

none,  198 
-iodo-phenolphthalein,  182 

-pyrrol,  176 
-methoxy-dioxy-gallic    anthra- 

quinone,  203 
Tetramethyl  -  diamino  -  dimethyl  - 

carbinol,  103 
-diamino  -   dimethyl  -  ethyl  - 

carbinol,  102 

1.3.7. 8-Tetramethyl-xanthine,    231, 
235 


INDEX 


331 


Tetranitrin,  227 

Tetronal,  32,  35 

Thalleioquin,  78 

Theobroma  Cacao,  245 

Theobromine,  245 

Theocin,  239 

Theophyllin,  239 

Thiocol,  161 

Thiosinamin,  294 

Thymol,  164 

Thymus  vulgaris,  164 

Thyroid  gland,  304 

Thyroxin,  preparation  of,  305 

Toluene-o-sulphonic  acid,  321 

sulphonamide,  electrolytic  oxi- 
dation of,  319 
-o-sulphonamide,  135 
-/?-sulphonamide,      107,      167- 

168 

-o-sulphonchloride,  311 
-£-sulphonchloride,  167,  313 
-sulphondichloramine,  170 
-sulphondiethylamide,  107 

Tribromphenol,  173 

Trichlor-8-methyl  caffeine,  231 

8-Trichlormethyl-caffeine,  235 

Trichlor-tertiary-butyl-alcohol,  30 

Trigonelline,  309 

1.2. 7-Trihydroxy-anthraquinone, 
197 

1.3.7-Trimethyl  uric  acid,  231 

Trimethyl-xanthine/  230 

Trinitriri,  226 

Trional,  32,  35 

Triphenyl-stibine-sulphide,  277 


Tropacocaine,  95 

hydrochloride,  96 
Tropine,  95 
Tyramine,  211,  214 

UREA,  43 

derivatives  of,  36 
Urethane,  37 
Urginea  Scilla,  291 
Uric  acid,  231 
Urotropine,  187 

VACUUM  dryer  (diagram),  134,  135 
still,  (diagram),  200 

oil-jacketed  (diagram),  73 
with  stirrer  (diagram),  120 

Vaso-constrictors,  211 

Vaso-dilators,  211 

Veratrol,  221 

Veronal,  43 

Veronal-sodium,  45 

Vinyl-diacetonamine  oxalate,  98 
-diacetone-alkamine,  98 
hydrochloride,  benzoylation  of, 
99 

Virgin  Scammony,  207 

Vitamines,  307 

WATER-soluble  B.  vitamine,  308 

extract,  310 
Wood  spirit,  183 

XEROFORM,  173 


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